Modulators of estrogen receptor proteolysis and associated methods of use

ABSTRACT

The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/810,764, filed 5 Mar. 2020, published as U.S. PatentApplication Publication No. 2020/0199107, which is a divisionalapplication of U.S. patent application Ser. No. 15/881,318, filed 26Jan. 2018, published as U.S. Pat. No. 10,604,506, which claims priorityto and the benefit of U.S. Provisional Patent Application No.62/450,740, filed 26 Jan. 2017, and U.S. Provisional Patent ApplicationNo. 62/587,378, filed 16 Nov. 2017, each of which is titled MODULATORSOF ESTROGEN RECEPTOR PROTEOLYSIS AND ASSOCIATED METHODS OF USE andincorporated herein by reference in their entirety for all purposes.

INCORPORATION BY REFERENCE

U.S. patent application Ser. No. 15/230,354, filed on Aug. 5, 2016; andU.S. patent application Ser. No. 15/206,497 filed 11 Jul. 2016; and U.S.patent application Ser. No. 15/209,648 filed 13 Jul. 2016; and U.S.patent application Ser. No. 15/730,728, filed on Oct. 11, 2017; and U.S.patent application Ser. No. 14/686,640, filed on Apr. 14, 2015,published as U.S. Patent Application Publication No. 2015/0291562; andU.S. patent application Ser. No. 14/792,414, filed on Jul. 6, 2015,published as U.S. Patent Application Publication No. 2016/0058872; andU.S. patent application Ser. No. 14/371,956, filed on Jul. 11, 2014,published as U.S. Patent Application Publication No. 2014/0356322; andU.S. patent application Ser. No. 15/074,820, filed on Mar. 18, 2016,published as U.S. Patent Application Publication No. 2016/0272639; andU.S. Patent Application Ser. No. 62/452,972, filed Jan. 31, 2017; andU.S. patent application Ser. No. 15/706,064, filed on Sep. 15, 2017,entitled “INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADES”, filed Jan.31, 2017; and International Patent Application No. PCT/US2016/023258,filed Mar. 18, 2016, published as International Patent ApplicationPublication No. WO2016/149668, are incorporated herein by reference intheir entirety. Furthermore, all references cited herein areincorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The description provides bifunctional compounds comprising a targetprotein binding moiety and an E3 ubiquitin ligase binding moiety, andassociated methods of use. The bifunctional compounds are useful asmodulators of targeted ubiquitination, especially with respect toestrogen receptor (ER), which are degraded and/or otherwise inhibited bybifunctional compounds according to the present disclosure, and thetreatment of disease and conditions mediated by the ER, e.g. thetreatment of breast cancer.

BACKGROUND

The estrogen receptor (ER) is a member of the nuclear hormone receptorfamily and functions as a ligand-activated transcription factor involvedwith the up and down regulation of gene expression. The natural hormonefor the estrogen receptor is 17-beta-estradiol (E2) and closely relatedmetabolites. Binding of estradiol to the estrogen receptor causes adimerization of the receptor and the dimer in turn binds to estrogenresponse elements (ERE's) on DNA. The ER-DNA complex recruits othertranscription factors responsible for the transcription of DNAdownstream from the ERE into mRNA, which is eventually translated intoprotein. Alternatively, the interaction of ER with DNA may be indirectthrough the intermediacy of other transcription factors, most notablyfos and jun. Since the expression of a large number of genes isregulated by the estrogen receptor and since the estrogen receptor isexpressed in many cell types, modulation of the estrogen receptorthrough binding of either natural hormones or synthetic ER ligands canhave profound effects on the physiology and pathophysiology of theorganism.

A variety of diseases have their etiology and/or pathology mediated bythe ER. Collectively these diseases are called estrogen-dependentdiseases. Estrogens are critical for sexual development in females. Inaddition, estrogens play an important role in maintaining bone density,regulation of blood lipid levels, and appear to have neuroprotectiveeffects. Consequently, decreased estrogen production in post-menopausalwomen is associated with a number of diseases such as osteoporosis,atherosclerosis, depression and cognitive disorders. Conversely, certaintypes of proliferative diseases such as breast and uterine cancer andendometriosis are stimulated by estrogens and therefore antiestrogens(i.e. estrogen antagonists) have utility in the prevention and treatmentof these types of disorders.

There are two different forms of the estrogen receptor, usually referredto as α and β, each encoded by a separate gene (ESR1 and ESR2,respectively). Both ERs are widely expressed in different tissue types,but there are some notable differences in their expression patterns. TheERα is found in endometrium, breast cancer cells, ovarian stroma cells,and the hypothalamus. In males, ERα protein is found in the epitheliumof the efferent ducts. The expression of the ERβ protein has beendocumented in kidney, brain, bone, heart, lungs, intestinal mucosa,prostate, and endothelial cells. Development therefore of selectiveligands may therefore preserve the beneficial aspects of estrogen.

Breast cancer is the most common malignancy to affect women andworldwide, the incidence of the disease is increasing. Estrogens, inparticular, act as endocrine growth factors for at least one-third ofbreast cancers, and depriving the tumor of this stimulus is a recognizedtherapy for advanced disease in premenopausal women, this is achieved bythe ablation of ovarian function through surgical, radio therapeutics,or medical means and, in postmenopausal women, by the use of aromataseinhibitors.

An alternative approach to estrogen withdrawal is to antagonize estrogenwith antiestrogens. These are drugs that bind to and compete forestrogen receptors (ER) present in estrogen-responsive tissue.Conventional nonsteroidal antiestrogens, such as tamoxifen, competeefficiently for ER binding but their effectiveness is often limited bythe partial agonism they display, which results in an incompleteblockade of estrogen-mediated activity. A specific or “pure”antiestrogen with high affinity for ER and without any agonist effectmay have advantages over conventional nonsteroidal anti-estrogens in thetreatment of estrogen-dependent disease. Fulvestrant is the first of anew class of potent pure anti-estrogens and is completely free of thepartial agonist, estrogen-like activity, associated with currentlyavailable antiestrogens like tamoxifen.

As such, there is a need for other approaches to antagonize the ERreceptor. One approach would be to develop selective ER down regulatorsor degraders that reduce ER expression at either the transcript orprotein level.

Several methods are available for the manipulation of protein levels,including proteolysis targeting chimeric molecules (PROTACs), whichcontain a ligand that recognizes the target protein linked to a ligandthat binds to a specific E3 ubiquitin ligase. It would be desirable tohave a small molecule which can simultaneously bind ER and an E3ubiquitin ligase and which promotes ubiquitination of ER and leads todegradation of ER by the proteasome.

Most small molecule drugs bind enzymes or receptors in tight andwell-defined pockets. On the other hand, protein-protein interactionsare notoriously difficult to target using small molecules due to theirlarge contact surfaces and the shallow grooves or flat interfacesinvolved. E3 ubiquitin ligases (of which hundreds are known in humans)confer substrate specificity for ubiquitination, and therefore, are moreattractive therapeutic targets than general proteasome inhibitors due totheir specificity for certain protein substrates. The development ofligands of E3 ligases has proven challenging, in part due to the factthat they must disrupt protein-protein interactions. However, recentdevelopments have provided specific ligands which bind to these ligases.For example, since the discovery of nutlins, the first small molecule E3ligase inhibitors, additional compounds have been reported that targetE3 ligases but the field remains underdeveloped. For example, since thediscovery of Nutlins, the first small molecule E3 ligase mouse doubleminute 2 homolog (MDM2) inhibitors, additional compounds have beenreported that target MDM2 (i.e., human double minute 2 or HDM2) E3ligases (J. Di, et al. Current Cancer Drug Targets (2011), 11(8),987-994).

Tumor suppressor gene p53 plays an important role in cell growth arrestand apoptosis in response to DNA damage or stress (A. Vazquez, et al.Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 hasbeen suggested as one of the major pathway for tumor cell survival (A.J. Levine, et al. Nature (2000), 408, 307-310). In cancer patients,about 50% were found with p53 mutation (M. Hollstein, et al. Science(1991), 233, 49-53), while patients with wild type p53 were often foundp53 down regulation by MDM2 through the protein-protein interaction ofp53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109).Under normal cell condition without oncogenic stress signal, MDM2 keepsp53 at low concentration. In response to DNA damage or cellular stress,p53 level increases, and that also causes increase in MDM2 due to thefeedback loop from p53/MDM2 auto regulatory system. In other words, p53regulates MDM2 at the transcription level, and MDM2 regulates p53 at itsactivity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

Several mechanisms can explain p53 down regulation by MDM2. First, MDM2binds to N-terminal domain of p53 and blocks expression ofp53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245).Second, MDM2 shuttles p53 from nucleus to cytoplasm to facilitateproteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564).Lastly, MDM2 carries intrinsic E3 ligase activity of conjugatingubiquitin to p53 for degradation through ubiquitin-dependent 26sproteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299).As such, because MDM2 functions as E3 ligase, recruiting MDM2 to adisease causing protein and effectuating its ubiquitination anddegradation is an approach of high interest for drug discovery.

One E3 ligase with exciting therapeutic potential is the vonHippel-Lindau (VHL) tumor suppressor, the substrate recognition subunitof the E3 ligase complex VCB, which also consists of elongins B and C,Cul2 and Rbx1. The primary substrate of VHL is Hypoxia Inducible Factor1α (HIF-1α), a transcription factor that upregulates genes such as thepro-angiogenic growth factor VEGF and the red blood cell inducingcytokine erythropoietin in response to low oxygen levels. The firstsmall molecule ligands of Von Hippel Lindau (VHL) to the substraterecognition subunit of the E3 ligase were generated, and crystalstructures were obtained confirming that the compound mimics the bindingmode of the transcription factor HIF-1α, the major substrate of VHL.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

Thalidomide, which has been approved for the treatment of a number ofimmunological indications, has also been approved for the treatment ofcertain neoplastic diseases, including multiple myeloma. In addition tomultiple myeloma, thalidomide and several of its analogs are alsocurrently under investigation for use in treating a variety of othertypes of cancer. While the precise mechanism of thalidomide's anti-tumoractivity is still emerging, it is known to inhibit angiogenesis. Recentliterature discussing the biology of the imides includes Lu et al.Science 343, 305 (2014) and Krönke et al. Science 343, 301 (2014).

Significantly, thalidomide and its analogs e.g. pomolinamiode andlenalinomide, are known to bind cereblon. These agents bind to cereblon,altering the specificity of the complex to induce the ubiquitination anddegradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factorsessential for multiple myeloma growth. Indeed, higher expression ofcereblon has been linked to an increase in efficacy of imide drugs inthe treatment of multiple myeloma.

Inhibitors of Apotosis Proteins (IAPs) are a protein family involved insuppressing apoptosis, i.e. cell death. The human IAP family includes 8members, and numerous other organisms contain IAP homologs. IAPs containan E3 ligase specific domain and baculoviral IAP repeat (BIR) domainsthat recognize substrates, and promote their ubiquitination. IAPspromote ubiquitination and can directly bind and inhibit caspases.Caspases are proteases (e.g. caspase-3, caspase-7 and caspace-9) thatimplement apoptosis. As such, through the binding of caspases, IAPsinhibit cell death. However, pro-apoptotic stimuli can result in therelease of mitochondrial proteins DIABLO (also known as secondmitrochondria-derived activator of caspases or SMAC) and HTRA2 (alsoknown as Omi). Binding of DIABLO and HTRA2 appears to block IAPactivity.

SMAC interacts with essentially all known IAPs including XIAP, c-IAP1,c-IAP2, NIL-IAP, Bruce, and survivin. The first four amino acids (AVPI)of mature SMAC bind to a portion of IAPs, which is believed to beessential for blocking the anti-apoptotic effects of IAPs.

Bifunctional compounds such as those that are described in U.S. PatentApplication Publications 2015-0291562 and 2014-0356322 (incorporatedherein by reference), function to recruit endogenous proteins to an E3ubiquiuin ligase for degradation. In particular, the publicationsdescribe bifunctional or proteolysis targeting chimeric (PROTAC)compounds, which find utility as modulators of targeted ubiquitinationof a variety of polypeptides and other proteins (such as estrogenreceptor), which are then degraded and/or otherwise inhibited by thebifunctional compounds.

An ongoing need exists in the art for effective treatments for diseaseassociated with overexpression or aggregation of ER. However,non-specific effects, and the inability to target and modulate ER,remain as obstacles to the development of effective treatments. As such,small-molecule therapeutic agents that target ER and that leverage orpotentiate cereblon's, MDM2's, and IAPs' substrate specificity would bevery useful.

SUMMARY

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of a variety of polypeptides and other proteins, such asestrogen receptor, which are then degraded and/or otherwise inhibited bythe bifunctional compounds as described herein. An advantage of thecompounds provided herein is that a broad range of pharmacologicalactivities is possible, consistent with the degradation/inhibition oftargeted polypeptides from virtually any protein class or family. Inaddition, the description provides methods of using an effective amountof the compounds as described herein for the treatment or ameliorationof a disease condition, such as cancer, e.g., breast cancer.

As such, in one aspect the disclosure provides bifunctional or PROTACcompounds, which comprise an E3 ubiquitin ligase binding moiety (i.e., aligand for an E3 ubquitin ligase or “ULM” group), and a moiety thatbinds a target protein (i.e., a protein/polypeptide targeting ligand or“PTM” group) such that the target protein/polypeptide is placed inproximity to the ubiquitin ligase to effect degradation (and inhibition)of that protein. In a preferred embodiment, the ULM (ubiquitinationligase modulator) can be Von Hippel-Lindau E3 ubiquitin ligase (VHL)binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety(CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligasebinding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety(i.e., a “ILM”). For example, the structure of the bifunctional compoundcan be depicted as:

The respective positions of the PTM and ULM moieties (e.g., VLM, CLM,MLM or ILM) as well as their number as illustrated herein is provided byway of example only and is not intended to limit the compounds in anyway. As would be understood by the skilled artisan, the bifunctionalcompounds as described herein can be synthesized such that the numberand position of the respective functional moieties can be varied asdesired.

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). In this example, the structure of thebifunctional compound can be depicted as:

where PTM is a protein/polypeptide targeting moiety, L is a linker,e.g., a bond or a chemical group coupling PTM to ULM, and ULM is a IAPE3 ubiquitin ligase binding moiety, or a Von Hippel-Lindau E3 ubiquitinligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligasebinding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3ubiquitin ligase binding moiety (MLM).

For example, the structure of the bifunctional compound can be depictedas:

wherein: PTM is a protein/polypeptide targeting moiety; “L” is a linker(e.g. a bond or a chemical linker group) coupling the PTM and at leastone of VLM, CLM, MLM, ILM, or a combination thereof; VLM is VonHippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3ligase; CLM is cereblon E3 ubiquitin ligase binding moiety that binds tocereblon; MLM is an MDM2 E3 ubiquitin ligase binding moiety; and ILM isa IAP binding moiety which binds to IAP.

In certain preferred embodiments, the ILM is an AVPI tetrapeptidefragment. As such, in certain additional embodiments, the ILM of thebifunctional compound comprises the amino acids alanine (A), valine (V),proline (P), and isoleucine (I) or their unnatural mimetics,respectively. In additional embodiments, the amino acids of the AVPItetrapeptide fragment are connected to each other through amide bonds(i.e., —C(O)NH— or —NHC(O)—).

In certain embodiments, the compounds as described herein comprisemultiple independently selected ULMs, multiple PTMs, multiple chemicallinkers or a combination thereof.

In certain embodiments, ILM comprises chemical moieties such as thosedescribed herein.

In additional embodiments, VLM can be hydroxyproline or a derivativethereof. Furthermore, other contemplated VLMs are included in U.S.Patent Application Publication No. 2014/03022523, which as discussedabove, is incorporated herein in its entirety.

In an embodiment, the CLM comprises a chemical group derived from animide, a thioimide, an amide, or a thioamide. In a particularembodiment, the chemical group is a phthalimido group, or an analog orderivative thereof. In a certain embodiment, the CLM is thalidomide,lenalidomide, pomalidomide, analogs thereof, isosteres thereof, orderivatives thereof. Other contemplated CLMs are described in U.S.Patent Application Publication No. 2015/0291562, which is incorporatedherein in its entirety.

In certain embodiments, MLM can be nutlin or a derivative thereof.Furthermore, other contemplated MLMs are included in U.S. patentapplication Ser. No. 15/206,497 filed 11 Jul. 2016, which as discussedabove, is incorporated herein in its entirety. In certain additionalembodiments, the MLM of the bifunctional compound comprises chemicalmoieties such as substituted imidazolines, substitutedspiro-indolinones, substituted pyrrolidines, substituted piperidinones,substituted morpholinones, substituted pyrrolopyrimidines, substitutedimidazolopyridines, substituted thiazoloimidazoline, substitutedpyrrolopyrrolidinones, and substituted isoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In certain embodiments, “L” is a bond. In additional embodiments, thelinker “L” is a connector with a linear non-hydrogen atom number in therange of 1 to 20. The connector “L” can contain, but not limited to thefunctional groups such as ether, amide, alkane, alkene, alkyne, ketone,hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linkercan contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclicmoieties. Substitution with halogen, such as Cl, F, Br and I can beincluded in the linker. In the case of fluorine substitution, single ormultiple fluorines can be included.

In certain embodiments, VLM is a derivative of trans-3-hydroxyproline,where both nitrogen and carboxylic acid in trans-3-hydroxyproline arefunctionalized as amides.

In certain embodiments, CLM is a derivative of piperidine-2,6-dione,where piperidine-2,6-dione can be substituted at the 3-position, and the3-substitution can be bicyclic hetero-aromatics with the linkage as C—Nbond or C—C bond. Examples of CLM can be, but not limited to,pomalidomide, lenalidomide and thalidomide and their derivatives.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation and/orinhibition in a patient or subject, for example, an animal such as ahuman, and can be used for treating or ameliorating disease states orconditions which are modulated through the degraded/inhibited protein.In certain embodiments, the therapeutic compositions as described hereinmay be used to effectuate the degradation of proteins of interest forthe treatment or amelioration of a disease, e.g., cancer. In yet anotheraspect, the present disclosure provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising an ILM and a PTM, a PTM and a VLM, or aPTM and a CLM, or a PTM and a MLM, preferably linked through a linkermoiety, as otherwise described herein, wherein the VLM/ILM/CLM/MLM iscoupled to the PTM through a linker to target protein that binds to PTMfor degradation. Similarly, the PTM can be coupled to VLM or CLM or MLMor ILM through a linker to target a protein or polypeptide fordegradation. Degradation of the target protein will occur when thetarget protein is placed in proximity to the E3 ubiquitin ligase, thusresulting in degradation/inhibition of the effects of the target proteinand the control of protein levels. The control of protein levelsafforded by the present disclosure provides treatment of a disease stateor condition, which is modulated through the target protein by loweringthe level of that protein in the cells of a patient.

In still another aspect, the description provides methods for treatingor ameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,wherein the composition is effective for treating or ameliorating thedisease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentdisclosure will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the disclosure may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional aspects and embodiments areexpressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the disclosure, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentdisclosure and, together with the description, serve to explain theprinciples of the disclosure. The drawings are only for the purpose ofillustrating an embodiment of the disclosure and are not to be construedas limiting the disclosure. Further objects, features and advantages ofthe disclosure will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the disclosure, in which:

FIGS. 1A and 1B. Illustration of general principle for PROTAC function.(FIG. 1A) Exemplary PROTACs comprise a protein targeting moiety (PTM;darkly shaded rectangle), a ubiquitin ligase binding moiety (ULM;lightly shaded triangle), and optionally a linker moiety (L; black line)coupling or tethering the PTM to the ULM. (FIG. 1B) Illustrates thefunctional use of the PROTACs as described herein. Briefly, the ULMrecognizes and binds to a specific E3 ubiquitin ligase, and the PTMbinds and recruits a target protein bringing it into close proximity tothe E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexedwith an E2 ubiquitin-conjugating protein, and either alone or via the E2protein catalyzes attachment of ubiquitin (dark circles) to a lysine onthe target protein via an isopeptide bond. The poly-ubiquitinatedprotein (far right) is then targeted for degradation by the proteosomalmachinery of the cell.

FIG. 2A. Degradation of ERα by Compound 11 in MCF7 cells after a 24 hourincubation: column 1, DMSO control; column 2, 3 μM pomalidomide; column3, 30 nM Compound 11 plus 3 μM pomalidomide; column 4, 30 nM Compound11; column 5, 300 nM Compound 11; column 6, 30 nM Compound 11; andcolumn 7, 3 nM Compound 11.

FIG. 2B. Degradation of ERα by Fulvestrant, Compound 140, Compound 152,AZD9496, RAD1901, and GDC810 in T47D cells after a 24 hour incubation.Concentrations for all compounds are 6, 25 and 100 nM.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present disclosure. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

Presently described are compositions and methods that relate to thesurprising and unexpected discovery that an E3 ubiquitin ligase protein(e.g., inhibitors of apoptosis proteins (IAP), a Von Hippel-Lindau E3ubiquitin ligase (VHL), a cereblon E3 ubiquitin ligase, or a mousedouble minute 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinates atarget protein once it and the target protein are placed in proximity bya bifunctional or chimeric construct that binds the E3 ubiquitin ligaseprotein and the target protein. Accordingly the present disclosureprovides such compounds and compositions comprising an E3 ubiquintinligase binding moiety (“ULM”) coupled to a protein target binding moiety(“PTM”), which result in the ubiquitination of a chosen target protein(such as estrogen receptor [ER]), which leads to degradation of thetarget protein by the proteasome (see FIGS. 1A and 1B). The presentdisclosure also provides a library of compositions and the use thereof.

In certain aspects, the present disclosure provides compounds whichcomprise a ligand, e.g., a small molecule ligand (i.e., having amolecular weight of below 2,000, 1,000, 500, or 200 Daltons), which iscapable of binding to a ubiquitin ligase, such as IAP, VHL, MDM2, orcereblon. The compounds also comprise a moiety that is capable ofbinding to target protein, in such a way that the target protein isplaced in proximity to the ubiquitin ligase to effect degradation(and/or inhibition) of that protein. Small molecule can mean, inaddition to the above, that the molecule is non-peptidyl, that is, it isnot generally considered a peptide, e.g., comprises fewer than 4, 3, or2 amino acids. In accordance with the present description, the PTM, ULMor PROTAC molecule can be a small molecule.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the disclosure.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the disclosure. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the disclosure, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the disclosure.

The following terms are used to describe the present disclosure. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present disclosure.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anonlimiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” refer to both concurrent administration (administration of twoor more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are coadministered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects, theco-administration of compounds results in synergistic activity and/ortherapy, including anticancer activity.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives, including prodrug and/or deuteratedforms thereof where applicable, in context. Deuterated small moleculescontemplated are those in which one or more of the hydrogen atomscontained in the drug molecule have been replaced by deuterium.

Within its use in context, the term compound generally refers to asingle compound, but also may include other compounds such asstereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, in context toprodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. It isnoted that in describing the present compounds, numerous substituentsand variables associated with same, among others, are described. It isunderstood by those of ordinary skill that molecules which are describedherein are stable compounds as generally described hereunder. When thebond is shown, both a double bond and single bond are represented orunderstood within the context of the compound shown and well-known rulesfor valence interactions.

The term “ubiquitin ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, IAP an E3ubiquitin ligase protein that alone or in combination with an E2ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule.Mono-ubiquitinated proteins are not targeted to the proteasome fordegradation, but may instead be altered in their cellular location orfunction, for example, via binding other proteins that have domainscapable of binding ubiquitin. Further complicating matters, differentlysines on ubiquitin can be targeted by an E3 to make chains. The mostcommon lysine is Lys48 on the ubiquitin chain. This is the lysine usedto make polyubiquitin, which is recognized by the proteasome.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a human or a domesticated animal, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent disclosure, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term effective subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

Compounds and Compositions

In one aspect, the description provides compounds comprising an E3ubiquitin ligase binding moiety (“ULM”) that is an IAP E3 ubiquitinligase binding moiety (an “ILM”), a cereblon E3 ubiquitin ligase bindingmoiety (a “CLM”), a Von Hippel-Lindae E3 ubiquitin ligase (VHL) bindingmoiety (VLM), and/or a mouse double minute 2 homologue (MDM2) E3ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, theULM is coupled to a target protein binding moiety (PTM) via a chemicallinker (L) according to the structure:

PTM-L-ULM  (A)

wherein L is a bond or a chemical linker group, ULM is a E3 ubiquitinligase binding moiety, and PTM is a target protein binding moiety. Thenumber and/or relative positions of the moieties in the compoundsillustrated herein is provided by way of example only. As would beunderstood by the skilled artisan, compounds described herein can besynthesized with any desired number and/or relative position of therespective functional moieties.

The terms ULM, ILM, VLM, MLM, and CLM are used in their inclusive senseunless the context indicates otherwise. For example, the term ULM isinclusive of all ULMs, including those that bind IAP (i.e., ILMs), MDM2(i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Further, theterm ILM is inclusive of all possible IAP E3 ubiquitin ligase bindingmoieties, the term MLM is inclusive of all possible MDM2 E3 ubiquitinligase binding moieties, the term VLM is inclusive of all possible VHLbinding moieties, and the term CLM is inclusive of all cereblon bindingmoieties.

In another aspect, the present disclosure provides bifunctional ormultifunctional compounds (e.g., PROTACs) useful for regulating proteinactivity by inducing the degradation of a target protein. In certainembodiments, the compound comprises an ILM or a VLM or a CLM or a MLMcoupled, e.g., linked covalently, directly or indirectly, to a moietythat binds a target protein (i.e., a protein targeting moiety or a“PTM”). In certain embodiments, the ILM/VLM/CLM/MLM and PTM are joinedor coupled via a chemical linker (L). The ILM binds the IAP E3 ubiquitinligase, the VLM binds VHL, CLM binds the cereblon E3 ubiquitin ligase,and MLM binds the MDM2 E3 ubiquitin ligase, and the PTM recognizes atarget protein and the interaction of the respective moieties with theirtargets facilitates the degradation of the target protein by placing thetarget protein in proximity to the ubiquitin ligase protein. Anexemplary bifunctional compound can be depicted as:

PTM-ILM  (B)

PTM-CLM  (C)

PTM-VLM  (D)

PTM-MLM  (E)

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). For example, the bifunctional compound can bedepicted as:

PTM-L-ILM  (F)

PTM-L-CLM  (G)

PTM-L-VLM  (H)

PTM-L-MLM  (I)

wherein the PTM is a protein/polypeptide targeting moiety, the L is achemical linker, the ILM is a IAP E3 ubiquitin ligase binding moiety,the CLM is a cereblon E3 ubiquitin ligase binding moiety, the VLM is aVHL binding moiety, and the MLM is a MDM2 E3 ubiquitin ligase bindingmoiety.

In certain embodiments, the ULM (e.g., a ILM, a CLM, a VLM, or a MLM)shows activity or binds to the E3 ubiquitin ligase (e.g., IAP E3ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3ubiquitin ligase) with an IC₅₀ of less than about 200 PM. The IC₅₀ canbe determined according to any method known in the art, e.g., afluorescent polarization assay.

In certain additional embodiments, the bifunctional compounds describedherein demonstrate an activity with an IC₅₀ of less than about 100, 50,10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100,50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less thanabout 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

In certain embodiments, the compounds as described herein comprisemultiple PTMs (targeting the same or different protein targets),multiple ULMs, one or more ULMs (i.e., moieties that bind specificallyto multiple/different E3 ubiquitin ligase, e.g., VHL, IAP, cereblon,and/or MDM2) or a combination thereof. In any of the aspects orembodiments described herein, the PTMs and ULMs (e.g., ILM, VLM, CLM,and/or MLM) can be coupled directly or via one or more chemical linkersor a combination thereof. In additional embodiments, where a compoundhas multiple ULMs, the ULMs can be for the same E3 ubiquintin ligase oreach respective ULM can bind specifically to a different E3 ubiquitinligase. In still further embodiments, where a compound has multiplePTMs, the PTMs can bind the same target protein or each respective PTMcan bind specifically to a different target protein.

In certain embodiments, where the compound comprises multiple ULMs, theULMs are identical. In additional embodiments, the compound comprising aplurality of ULMs (e.g., ULM, ULM′, etc.), at least one PTM coupled to aULM directly or via a chemical linker (L) or both. In certain additionalembodiments, the compound comprising a plurality of ULMs furthercomprises multiple PTMs. In still additional embodiments, the PTMs arethe same or, optionally, different. In still further embodiments,wherein the PTMs are different, the respective PTMs may bind the sameprotein target or bind specifically to a different protein target.

In certain embodiments, the compound may comprise a plurality of ULMsand/or a plurality of ULM's. In further embodiments, the compoundcomprising at least two different ULMs, a plurality of ULMs, and/or aplurality of ULM's further comprises at least one PTM coupled to a ULMor a ULM′ directly or via a chemical linker or both. In any of theembodiments described herein, a compound comprising at least twodifferent ULMs can further comprise multiple PTMs. In still additionalembodiments, the PTMs are the same or, optionally, different. In stillfurther embodiments, wherein the PTMs are different the respective PTMsmay bind the same protein target or bind specifically to a differentprotein target. In still further embodiments, the PTM itself is a ULM(or ULM′), such as an ILM, a VLM, a CLM, a MLM, an ILM′, a VLM′, a CLM′,and/or a MLM′.

In additional embodiments, the description provides the compounds asdescribed herein including their enantiomers, diastereomers, solvatesand polymorphs, including pharmaceutically acceptable salt formsthereof, e.g., acid and base salt forms.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C₁-C₃ alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl andcyclohexyl, among others. In certain embodiments, the alkyl group isend-capped with a halogen group (At, Br, Cl, F, or I). In certainpreferred embodiments, compounds according to the present disclosurewhich may be used to covalently bind to dehalogenase enzymes. Thesecompounds generally contain a side chain (often linked through apolyethylene glycol group) which terminates in an alkyl group which hasa halogen substituent (often chlorine or bromine) on its distal endwhich results in covalent binding of the compound containing such amoiety to the protein.

The term “Alkenyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C═Cbond.

The term “Alkynyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C≡Cbond.

The term “alkylene” when used, refers to a —(CH₂)_(n)— group (n is aninteger generally from 0-6), which may be optionally substituted. Whensubstituted, the alkylene group preferably is substituted on one or moreof the methylene groups with a C₁-C₆ alkyl group (including acyclopropyl group or a t-butyl group), but may also be substituted withone or more halo groups, preferably from 1 to 3 halo groups or one ortwo hydroxyl groups, O—(C₁-C₆ alkyl) groups or amino acid sidechains asotherwise disclosed herein. In certain embodiments, an alkylene groupmay be substituted with a urethane or alkoxy group (or other group)which is further substituted with a polyethylene glycol chain (of from 1to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to whichis substituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. A range of carbon atoms which includes C₀ means that carbon isabsent and is replaced with H. Thus, a range of carbon atoms which isC₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C₀, H standsin place of carbon.

The term “substituted” or “optionally substituted” shall meanindependently (i.e., where more than substituent occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substitutents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present disclosure and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orCl), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted —N(C₀-C₆ alkyl)C(O)(O—C₁-C₆ alkyl) group (whichmay be optionally substituted with a polyethylene glycol chain to whichis further bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present disclosure mayinclude, for example —SiR₁R₂R₃ groups where each of R₁ and R₂ is asotherwise described herein and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R₃ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteraryl moiety) through an optionally substituted—(CH₂)_(m)— or alternatively an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m)— or —(CH₂CH₂O)_(m)— group, which may be substituted withany one or more of the above-described substituents. Alkylene groups—(CH₂)_(m)— or —(CH₂)_(n)— groups or other chains such as ethyleneglycol chains, as identified above, may be substituted anywhere on thechain. Preferred substitutents on alkylene groups include halogen orC₁-C₆ (preferably C₁-C₃) alkyl groups, which may be optionallysubstituted with one or two hydroxyl groups, one or two ether groups(O—C₁-C₆ groups), up to three halo groups (preferably F), or a sideshainof an amino acid as otherwise described herein and optionallysubstituted amide (preferably carboxamide substituted as describedabove) or urethane groups (often with one or two C₀-C₆ alkylsubstitutents, which group(s) may be further substituted). In certainembodiments, the alkylene group (often a single methylene group) issubstituted with one or two optionally substituted C₁-C₆ alkyl groups,preferably C₁-C₄ alkyl group, most often methyl or O-methyl groups or asidechain of an amino acid as otherwise described herein. In the presentdisclosure, a moiety in a molecule may be optionally substituted with upto five substituents, preferably up to three substituents. Most often,in the present disclosure moieties which are substituted are substitutedwith one or two substituents.

The term “substituted” (each substituent being independent of any othersubstituent) shall also mean within its context of use C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone, includingsulfonamide, keto, carboxy, C₁-C₆ ester (oxyester or carbonylester),C₁-C₆ keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R₁, nitro, cyano andamine (especially including a C₁-C₆ alkylene-NR₁R₂, a mono- or di-C₁-C₆alkyl substituted amines which may be optionally substituted with one ortwo hydroxyl groups). Each of these groups contain unless otherwiseindicated, within context, between 1 and 6 carbon atoms. In certainembodiments, preferred substituents will include for example, —NH—,—NHC(O)—, —O—, ═O, —(CH₂)_(m)— (here, m and n are in context, 1, 2, 3,4, 5 or 6), —S—, —S(O)—, SO₂— or —NH—C(O)—NH—, —(CH₂)_(n)OH,—(CH₂)_(n)SH, —(CH₂)_(n)COOH, C₁-C₆ alkyl, —(CH₂)_(n)O—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)—(C₁-C₆ alkyl), —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)O—(C₁-C₆ alkyl), —(CH₂)_(n)NHC(O)—R₁,—(CH₂)_(n)C(O)—NR₁R₂, —(OCH₂)_(n)OH, —(CH₂O)_(n)COOH, C₁-C₆ alkyl,—(OCH₂)_(n)O—(C₁-C₆ alkyl), —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),—(OCH₂)_(n)NHC(O)—R₁, —(CH₂O)_(n)C(O)—NR₁R₂, —S(O)₂—R_(S), —S(O)—R_(S)(R_(S) is C₁-C₆ alkyl or a —(CH₂)_(m)—NR₁R₂ group), NO₂, CN or halogen(F, Cl, Br, I, preferably F or Cl), depending on the context of the useof the substituent. R₁ and R₂ are each, within context, H or a C₁-C₆alkyl group (which may be optionally substituted with one or twohydroxyl groups or up to three halogen groups, preferably fluorine). Theterm “substituted” shall also mean, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substitutedC₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group O—C(O)—NR₁R₂ group where R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

The term “aryl” or “aromatic”, in context, refers to a substituted (asotherwise described herein) or unsubstituted monovalent aromatic radicalhaving a single ring (e.g., benzene, phenyl, benzyl) or condensed rings(e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound tothe compound according to the present disclosure at any available stableposition on the ring(s) or as otherwise indicated in the chemicalstructure presented. Other examples of aryl groups, in context, mayinclude heterocyclic aromatic ring systems, “heteroaryl” groups havingone or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic)such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrimidine, pyrazine, triazole, oxazole or fused ring systems such asindole, quinoline, indolizine, azaindolizine, benzofurazan, etc., amongothers, which may be optionally substituted as described above. Amongthe heteroaryl groups which may be mentioned include nitrogen-containingheteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine,pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine,tetrazole, indole, isoindole, indolizine, azaindolizine, purine,indazole, quinoline, dihydroquinoline, tetrahydroquinoline,isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,acridine, phenanthridine, carbazole, carbazoline, pyrimidine,phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine,pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromaticheterocycles such as thiophene and benzothiophene; oxygen-containingaromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuranand isobenzofuran; and aromatic heterocycles comprising 2 or more heteroatoms selected from among nitrogen, sulfur and oxygen, such as thiazole,thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

The term “substituted aryl” refers to an aromatic carbocyclic groupcomprised of at least one aromatic ring or of multiple condensed ringsat least one of which being aromatic, wherein the ring(s) aresubstituted with one or more substituents. For example, an aryl groupcan comprise a substituent(s) selected from: —(CH₂)_(n)OH,—(CH₂)_(n)—O—(C₁-C₆)alkyl, —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl,—(CH₂)_(n)—C(O)(C₀-C₆) alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,—(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, Cl) groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is preferably connected to a PTM group,including a ULM group, via a linker group), and/or at least one of F,Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (in ortho-, meta-and/or para-positions of the phenyl ring, preferably para-), a naphthylgroup, which may be optionally substituted, an optionally substitutedheteroaryl, preferably an optionally substituted isoxazole including amethylsubstituted isoxazole, an optionally substituted oxazole includinga methylsubstituted oxazole, an optionally substituted thiazoleincluding a methyl substituted thiazole, an optionally substitutedisothiazole including a methyl substituted isothiazole, an optionallysubstituted pyrrole including a methylsubstituted pyrrole, an optionallysubstituted imidazole including a methylimidazole, an optionallysubstituted benzimidazole or methoxybenzylimidazole, an optionallysubstituted oximidazole or methyloximidazole, an optionally substituteddiazole group, including a methyldiazole group, an optionallysubstituted triazole group, including a methylsubstituted triazolegroup, an optionally substituted pyridine group, including a halo-(preferably, F) or methylsubstitutedpyridine group or an oxapyridinegroup (where the pyridine group is linked to the phenyl group by anoxygen), an optionally substituted furan, an optionally substitutedbenzofuran, an optionally substituted dihydrobenzofuran, an optionallysubstituted indole, indolizine or azaindolizine (2, 3, or4-azaindolizine), an optionally substituted quinoline, and combinationsthereof.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, whereas these generic substituents have meanings which areidentical with definitions of the corresponding groups defined herein.

The term “heteroaryl” or “hetaryl” can mean but is in no way limited toan optionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein:

-   -   S^(c) is CHR^(SS), NR^(URE), or O;    -   R^(HET) is H, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) is H, CN, NO₂, halo (preferably F or Cl), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups), optionally        substituted O—(C₁-C₆ alkyl) (preferably substituted with one or        two hydroxyl groups or up to three halo groups) or an optionally        substituted —C(O)(C₁-C₆ alkyl) (preferably substituted with one        or two hydroxyl groups or up to three halo groups);    -   R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a        —C(O)(C₁-C₆ alkyl), each of which groups is optionally        substituted with one or two hydroxyl groups or up to three        halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) is N or C—R^(YC), where R^(YC) is H, OH, CN, NO₂, halo        (preferably Cl or F), optionally substituted C₁-C₆ alkyl        (preferably substituted with one or two hydroxyl groups or up to        three halo groups (e.g. CF₃), optionally substituted O(C₁-C₆        alkyl) (preferably substituted with one or two hydroxyl groups        or up to three halo groups) or an optionally substituted        acetylenic group —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl        group (preferably C₁-C₃ alkyl).

The terms “aralkyl” and “heteroarylalkyl” refer to groups that compriseboth aryl or, respectively, heteroaryl as well as alkyl and/orheteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systemsaccording to the above definitions.

The term “arylalkyl” as used herein refers to an aryl group as definedabove appended to an alkyl group defined above. The arylalkyl group isattached to the parent moiety through an alkyl group wherein the alkylgroup is one to six carbon atoms. The aryl group in the arylalkyl groupmay be substituted as defined above.

The term “Heterocycle” refers to a cyclic group which contains at leastone heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) ornon-aromatic. Thus, the heteroaryl moieties are subsumed under thedefinition of heterocycle, depending on the context of its use.Exemplary heteroaryl groups are described hereinabove.

Exemplary heterocyclics include: azetidinyl, benzimidazolyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl,benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl,dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl,oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl,N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline,thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl,oxathiolanyl, thiane among others.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, SO-heteroaryl,—SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, oxo (═O), and—SO2-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxy-nitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

The term “cycloalkyl” can mean but is in no way limited to univalentgroups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. The term “substituted cycloalkyl” can mean butis in no way limited to a monocyclic or polycyclic alkyl group and beingsubstituted by one or more substituents, for example, amino, halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mercapto or sulfo, whereas these generic substituent groups havemeanings which are identical with definitions of the correspondinggroups as defined in this legend.

“Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group inwhich at least one ring carbon atom of its cyclic structure beingreplaced with a heteroatom selected from the group consisting of N, O, Sor P. “Substituted heterocycloalkyl” refers to a monocyclic orpolycyclic alkyl group in which at least one ring carbon atom of itscyclic structure being replaced with a heteroatom selected from thegroup consisting of N, O, S or P and the group is containing one or moresubstituents selected from the group consisting of halogen, alkyl,substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto orsulfo, whereas these generic substituent group have meanings which areidentical with definitions of the corresponding groups as defined inthis legend.

The term “hydrocarbyl” shall mean a compound which contains carbon andhydrogen and which may be fully saturated, partially unsaturated oraromatic and includes aryl groups, alkyl groups, alkenyl groups andalkynyl groups.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “lower alkyl” refers to methyl, ethyl or propyl

The term “lower alkoxy” refers to methoxy, ethoxy or propoxy.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn can independently be covalently coupled to alinker and/or a linker to which is attached one or more PTM, ULM, ILM orILM′ groups.

Exemplary CLMs

Neo-Imide Compounds

In one aspect the description provides compounds useful for bindingand/or inhibiting cereblon. In certain embodiments, the compound isselected from the group consisting of chemical structures:

wherein:

-   -   W of Formulas (a) through (f) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   X of Formulas (a) through (f) is independently selected from the        group O, S and H₂;    -   Y of Formulas (a) through (f) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (f) is independently selected from the        group O, and S or H₂ except that both X and Z cannot be H₂;    -   G and G′ of Formulas (a) through (f) are independently selected        from the group H, alkyl (linear, branched, optionally        substituted), OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl        optionally substituted with R′, and benzyl optionally        substituted with R′;    -   Q1-Q4 of Formulas (a) through (f) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (f) is independently selected from the        group H, alkyl (linear, branched, optionally substituted),        cycloalkyl, Cl and F;    -   R of Formulas (a) through (f) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, (—CR′O)_(n)R″, -aryl, -hetaryl, -alkyl (linear,        branched, optionally substituted), -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and —OCF₃    -   R′ and R″ of Formulas (a) through (f) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   n of Formulas (a) through (f) is an integer from 1-10 (e.g.,        1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);        of Formulas (a) through (f) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific; and    -   R_(n) of Formulas (a) through (f) comprises 1-4 independent        functional groups or atoms.

Exemplary CLMs

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (a) through (f) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   X of Formulas (a) through (f) is independently selected from the        group O, S and H2;    -   Y of Formulas (a) through (f) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (f) is independently selected from the        group O, and S or H2 except that both X and Z cannot be H2;    -   G and G′ of Formulas (a) through (f) are independently selected        from the group H, alkyl (linear, branched, optionally        substituted), OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl        optionally substituted with R′, and benzyl optionally        substituted with R′;    -   Q1-Q4 of Formulas (a) through (f) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (f) is independently selected from the        group H, alkyl (linear, branched, optionally substituted),        cycloalkyl, Cl and F;    -   R of Formulas (a) through (f) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO2R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF3, —CN, —NR′SO2NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO2)NR′R″, —SO2NR′COR″, —NO₂, —CO2R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3;    -   R′ and R″ of Formulas (a) through (f) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   n of Formulas (a) through (f) is an integer from 1-10 (e.g.,        1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);    -   of Formulas (a) through (f) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific; and    -   Rn of Formulas (a) through (f) comprises 1-4 independent        functional groups or atoms, and optionally, one of which is        modified to be covalently joined to a PTM, a chemical linker        group (L), a ULM, CLM (or CLM′) or combination thereof.

In certain embodiments described herein, the CLM or ULM comprises achemical structure selected from the group:

wherein:

-   -   W of Formula (g) is independently selected from the group CH₂,        C═O, NH, and N-alkyl;    -   R of Formula (g) is independently selected from a H, methyl, or        optionally substituted linear, branched, optionally substituted        alkyl [e.g., optionally substituted C1-C6 alkyl (linear,        branched, optionally substituted)];    -   of Formula (g) represents a bond that may be stereospecific ((R)        or (S)) or non-stereospecific; and    -   Rn of Formula (g) comprises 1-4 independently selected        functional groups or atoms, and optionally, one of which is        modified to be covalently joined to a PTM, a chemical linker        group (L), a ULM, CLM (or CLM′) or combination thereof.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn of Formulas (a) through (g) can independentlybe covalently coupled to a linker and/or a linker to which is attachedone or more PTM, ULM, CLM or CLM′ groups.

In any of the aspects or embodiments described herein, R_(n) comprisesfrom 1 to 4 functional groups or atoms, for example, O, OH, N, C1-C6alkyl, C1-C6 alkoxy, amine, amide, or carboxy, and optionally, one ofwhich is modified to be covalently joined to a PTM, a chemical linkergroup (L), a ULM, CLM (or CLM′) or combination thereof.

More specifically, non-limiting examples of CLMs include those shownbelow as well as those “hybrid” molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (h) through (ab) is independently selected from        CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   Q₁, Q₂, Q₃, Q₄, Q₅ of Formulas (h) through (ab) are        independently represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   R¹ of Formulas (h) through (ab) is selected from H, CN, C₁-C₃        alkyl;    -   R² of Formulas (h) through (ab) is selected from the group H,        CN, C₁-C₃ alkyl, CHF₂, CF₃, CHO;    -   R³ of Formulas (h) through (ab) is selected from H, alkyl,        substituted alkyl, alkoxy, substituted alkoxy;    -   R⁴ of Formulas (h) through (ab) is selected from H, alkyl,        substituted alkyl;    -   R⁵ of Formulas (h) through (ab) is H or lower alkyl;    -   X of Formulas (h) through (ab) is C, CH or N;    -   R′ of Formulas (h) through (ab) is selected from H, halogen,        alkyl, substituted alkyl, alkoxy, substituted alkoxy;    -   R of Formulas (h) through (ab) is H, OH, lower alkyl, lower        alkoxy, cyano, halogenated lower alkoxy, or halogenated lower        alkyl    -   of Formulas (h) through (ab) is a single or double bond; and    -   the CLM is covalently joined to a PTM, a chemical linker group        (L), a ULM, CLM (or CLM′) or combination thereof.

In any aspect or embodiment described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via an R group (such as, R, R¹, R², R³,R⁴ or R′), W, X, or a Q group (such as, Q₁, Q₂, Q₃, Q₄, or Q₅) ofFormulas (h) through (ab).

In any of the embodiments described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via W, X, R, R¹, R², R³, R⁴, R⁵, R′, Q₁,Q₂, Q₃, Q₄, and Q₅ of Formulas (h) through (ab).

In any of the embodiments described herein, the W, X, R¹, R², R³, R⁴,R′, Q₁, Q₂, Q₃, Q₄, and Q₅ of Formulas (h) through (ab) canindependently be covalently coupled to a linker and/or a linker to whichis attached to one or more PTM, ULM, ULM′, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as “hybrid” molecules or compounds that arise fromcombining 1 or more features of the following compounds:

wherein:

-   -   W of Formulas (ac) through (an) is independently selected from        the group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   R¹ of Formulas (ac) through (an) is selected from the group H,        CN, C1-C3 alkyl;    -   R³ of Formulas (ac) through (an) is selected from H, alkyl,        substituted alkyl, alkoxy, substituted alkoxy;    -   R of Formulas (ac) through (an) is H;    -   is a single or double bond; and    -   Rn of Formulas (ac) through (an) comprises a functional group or        an atom.

In any of the embodiments described herein, the W, R¹, R², Q₁, Q₂, Q₃,Q₄, and Rn of Formulas (ac) through (an) can independently be covalentlycoupled to a linker and/or a linker to which is attached one or morePTM, ULM, ULM′, CLM or CLM′ groups.

In any of the embodiments described herein, the R¹, R², Q₁, Q₂, Q₃, Q₄,and Rn of Formulas (ac) through (an) can independently be covalentlycoupled to a linker and/or a linker to which is attached one or morePTM, ULM, ULM′, CLM or CLM′ groups.

In any of the embodiments described herein, the Q₁, Q₂, Q₃, Q₄, and Rnof Formulas (ac) through (an) can independently be covalently coupled toa linker and/or a linker to which is attached one or more PTM, ULM,ULM′, CLM or CLM′ groups.

In any aspect or embodiment described herein, R_(n) of Formulas (ac)through (an) is modified to be covalently joined to the linker group(L), a PTM, a ULM, a second CLM having the same chemical structure asthe CLM, a CLM′, a second linker, or any multiple or combinationthereof.

In any aspect or embodiment described herein, the CLM is selected from:

wherein R′ is a halogen and R¹ is as described above with regard toFormulas (h) through (ab) or (ac) through (an).

In certain cases, the CLM can be imides that bind to cereblon E3 ligase.These imides and linker attachment point can be but not limited to thefollowing structures:

wherein R′ is a halogen.

Exemplary VLMs

In certain embodiments of the compounds as described herein, ULM is VLMand comprises a chemical structure selected from the group ULM-a:

wherein:

-   -   a dashed line indicates the attachment of at least one PTM,        another ULM or VLM or MLM or ILM or CLM (i.e., ULM′ or VLM′ or        CLM′ or ILM′ or MLM′), or a chemical linker moiety coupling at        least one PTM, a ULM′ or a VLM′ or a CLM′ or a ILM′ or a MLM′ to        the other end of the linker;    -   X¹, X² of Formula ULM-a are each independently selected from the        group of a bond, O, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and        SO₂;    -   R^(Y3), R^(Y4) of Formula ULM-a are each independently selected        from the group of H, linear or branched C₁₋₆ alkyl, optionally        substituted by 1 or more halo, optionally substituted C₁₋₆        alkoxyl (e.g., optionally substituted by 0-3 R^(P) groups);    -   R^(P) of Formula ULM-a is 0, 1, 2, or 3 groups, each        independently selected from the group H, halo, —OH, C₁₋₃ alkyl,        C═O;    -   W³ of Formula ULM-a is selected from the group of an optionally        substituted -T-N(R^(1a)R^(1b))X³, optionally substituted        -T-N(R^(1a)R^(1b)), optionally substituted -T-Aryl, an        optionally substituted -T-Heteroaryl, an optionally substituted        T-biheteroaryl, an optionally substituted -T-Heterocycle, an        optionally substituted -T-biheterocycle, an optionally        substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally substituted        —NR¹-T-Heterocycle;    -   X³ of Formula ULM-a is C═O, R¹, R^(1a), R^(1b);    -   each of R¹, R^(1a), R^(1b) is independently selected from the        group consisting of H, linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halo or —OH groups,        R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   T of Formula ULM-a is covalently bonded to X¹ and is selected        from the group of an optionally substituted alkyl, —(CH₂)_(n)—        group, wherein each one of the methylene groups is optionally        substituted with one or two substituents selected from the group        of halogen, methyl, a linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halogen or —OH groups or an        amino acid side chain optionally substituted;    -   W⁴ of Formula ULM-a is an optionally substituted —NR1-T-Aryl, an        optionally substituted —NR1-T-Heteroaryl group or an optionally        substituted —NR1-T-Heterocycle, where —NR1 is covalently bonded        to X² and R1 is H or CH3, preferably H.

In any of the embodiments described herein, T is selected from the groupof an optionally substituted alkyl, —(CH₂)_(n)— group, wherein each oneof the methylene groups is optionally substituted with one or twosubstituents selected from the group of halogen, methyl, a linear orbranched C₁-C₆ alkyl group optionally substituted by 1 or more halogenor —OH groups or an amino acid side chain optionally substituted; and nis 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

In certain embodiments, W⁴ of Formula ULM-a is

wherein R_(14a), R_(14b), are each independently selected from the groupof H, haloalkyl, or optionally substituted alkyl.

In any of the embodiments, W⁵ of Formula ULM-a is selected from thegroup of a phenyl or a 5-10 membered heteroaryl,

R₁₅ of Formula ULM-a is selected from the group of H, halogen, CN, OH,NO₂, NR_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted alkyl,optionally substituted haloalkyl, optionally substituted haloalkoxy;aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl (each optionallysubstituted);

In additional embodiments, W⁴ substituents for use in the presentdisclosure also include specifically (and without limitation to thespecific compound disclosed) the W⁴ substituents which are found in theidentified compounds disclosed herein. Each of these W⁴ substituents maybe used in conjunction with any number of W³ substituents which are alsodisclosed herein.

In certain additional embodiments, ULM-a, is optionally substituted by0-3 R^(P) groups in the pyrrolidine moiety. Each R^(P) is independentlyH, halo, —OH, C1-3alkyl, C═O.

In any of the embodiments described herein, the W³, W⁴ of Formula ULM-acan independently be covalently coupled to a linker which is attachedone or more PTM groups,

and wherein the dashed line indicates the site of attachment of at leastone PTM, another ULM (ULM′) or a chemical linker moiety coupling atleast one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM is VHL and is represented by the structure:

wherein:

-   -   W³ of Formula ULM-b is selected from the group of an optionally        substituted aryl, optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ of Formula ULM-b are independently hydrogen,        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted hydroxyalkyl, optionally substituted        heteroaryl, or haloalkyl, or R₉, R₁₀, and the carbon atom to        which they are attached form an optionally substituted        cycloalkyl;    -   R₁₁ of Formula ULM-b is selected from the group of an optionally        substituted heterocyclic, optionally substituted alkoxy,        optionally substituted heteroaryl, optionally substituted aryl,

-   -   R₁₂ of Formula ULM-b is selected from the group of H or        optionally substituted alkyl;    -   R₁₃ of Formula ULM-b is selected from the group of H, optionally        substituted alkyl, optionally substituted alkylcarbonyl,        optionally substituted (cycloalkyl)alkylcarbonyl, optionally        substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl;    -   R_(14a), R_(14b) of Formula ULM-b, are each independently        selected from the group of H, haloalkyl, or optionally        substituted alkyl;    -   W⁵ of Formula ULM-b is selected from the group of a phenyl or a        5-10 membered heteroaryl,    -   R₁₅ of Formula ULM-b is selected from the group of H, halogen,        CN, OH, NO₂, NR_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b),        NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b),        optionally substituted alkyl, optionally substituted haloalkyl,        optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl,        or cycloheteroalkyl (each optionally substituted);    -   R₁₆ of Formula ULM-b is independently selected from the group of        H, halo, optionally substituted alkyl, optionally substituted        haloalkyl, hydroxy, or optionally substituted haloalkoxy;    -   o of Formula ULM-b is 0, 1, 2, 3, or 4;    -   R₁₈ of Formula ULM-b is independently selected from the group of        H, halo, optionally substituted alkoxy, cyano, optionally        substituted alkyl, haloalkyl, haloalkoxy or a linker; and    -   p of Formula ULM-b is 0, 1, 2, 3, or 4; and    -   the dashed line indicates the site of attachment of at least one        PTM, another ULM (ULM′) or a chemical linker moiety coupling at        least one PTM or a ULM′ or both to ULM.

In certain embodiments, R₁₅ of Formula ULM-b is

wherein R₁₇ is H, halo, optionally substituted C₃₋₆cycloalkyl,optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆alkenyl,and C₁₋₆haloalkyl; and Xa is S or O.

In certain embodiments, R₁₇ of Formula ULM-b is selected from the groupmethyl, ethyl, isopropyl, and cyclopropyl.

In certain additional embodiments, R₁₅ of Formula ULM-b is selected fromthe group consisting of:

In certain embodiments, R₁₁ of Formula ULM-b is selected from the groupconsisting of:

In certain embodiments, ULM has a chemical structure selected from thegroup of:

wherein:

-   -   R₁ of Formulas ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl,        tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or        cyclohexyl; optionally substituted alkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl;    -   R_(14a) of Formulas ULM-c, ULM-d, and ULM-e is H, haloalkyl,        optionally substituted alkyl, methyl, fluoromethyl,        hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ of Formulas ULM-c, ULM-d, and ULM-e is selected from the        group consisting of H, halogen, CN, OH, NO₂, optionally        substituted heteroaryl, optionally substituted aryl; optionally        substituted alkyl, optionally substituted haloalkyl, optionally        substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl (each        optionally substituted);    -   X of Formulas ULM-c, ULM-d, and ULM-e is C, CH₂, or C═O    -   R₃ of Formulas ULM-c, ULM-d, and ULM-e is absent or an        optionally substituted 5 or 6 membered heteroaryl; and    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM comprises a group according to the chemicalstructure:

-   -   wherein:        -   R_(14a) of Formula ULM-f is H, haloalkyl, optionally            substituted alkyl, methyl, fluoromethyl, hydroxymethyl,            ethyl, isopropyl, or cyclopropyl;    -   R₉ of Formula ULM-f is H;    -   R₁₀ of Formula ULM-f is H, ethyl, isopropyl, tert-butyl,        sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R₁₁ of Formula ULM-f is

or optionally substituted heteroaryl;

-   -   p of Formula ULM-f is 0, 1, 2, 3, or 4;    -   each R₁₈ of Formula ULM-f is independently halo, optionally        substituted alkoxy, cyano, optionally substituted alkyl,        haloalkyl, haloalkoxy or a linker;    -   R₁₂ of Formula ULM-f is H, C═O;    -   R₁₃ of Formula ULM-f is H, optionally substituted alkyl,        optionally substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl,    -   R₁₅ of Formula ULM-f is selected from the group consisting of H,        halogen, Cl, CN, OH, NO₂, optionally substituted heteroaryl,        optionally substituted aryl;

-   -   the dashed line of Formula ULM-f indicates the site of        attachment of at least one PTM, another ULM (ULM′) or a chemical        linker moiety coupling at least one PTM or a ULM′ or both to        ULM.

In certain embodiments, the ULM is selected from the followingstructures:

In certain embodiments, the ULM is selected from the followingstructures:

wherein, the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 throughULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionallysubstituted with fluorine, lower alkyl and alkoxy groups, and whereinthe dashed line indicates the site of attachment of at least one PTM,another ULM (ULM′) or a chemical linker moiety coupling at least one PTMor a ULM′ or both to ULM-a.

In one embodiment, the phenyl ring in ULM-a1 through ULM-a15, ULM-b1through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 can befunctionalized as the ester to make it a part of the prodrug.

In certain embodiments, the hydroxyl group on the pyrrolidine ring ofULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15and ULM-d1 through ULM-d9, respectively, comprises an ester-linkedprodrug moiety.

In any of the aspects or embodiments described herein, the ULM and wherepresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R^(1′) of ULM-g is an optionally substituted C₁-C₆ alkyl group,        an optionally substituted —(CH₂)_(n)OH, an optionally        substituted —(CH₂)_(n)SH, an optionally substituted        (CH₂)_(n)—O—(C₁-C₆)alkyl group, an optionally substituted        (CH₂)_(n)—WCOCW—(C₀-C₆)alkyl group containing an epoxide moiety        WCOCW where each W is independently H or a C₁-C₃ alkyl group, an        optionally substituted —(CH₂)_(n)COOH, an optionally substituted        —(CH₂)C(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂)_(n)C(O)—NR₁R₂, an optionally substituted        —(CH₂)_(n)OC(O)—NR₁R₂, —(CH₂O)_(n)H, an optionally substituted        —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), an optionally substituted        —(CH₂O)_(n)COOH, an optionally substituted —(OCH₂)_(n)O—(C₁-C₆        alkyl), an optionally substituted —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),        an optionally substituted —(OCH₂)_(n)NHC(O)—R₁, an optionally        substituted —(CH₂O)_(n)C(O)—NR₁R₂, —(CH₂CH₂O)_(n)H, an        optionally substituted —(CH₂CH₂O)_(n)COOH, an optionally        substituted —(OCH₂CH₂)_(n)O—(C₁-C₆ alkyl), an optionally        substituted —(CH₂CH₂O)_(n)C(O)—(C₁-C₆ alkyl), an optionally        substituted —(OCH₂CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂CH₂O)_(n)C(O)—NR₁R₂, an optionally substituted —SO₂R_(S),        an optionally substituted S(O)R_(S), NO₂, CN or halogen (F, Cl,        Br, I, preferably F or Cl);    -   R₁ and R₂ of ULM-g are each independently H or a C₁-C₆ alkyl        group which may be optionally substituted with one or two        hydroxyl groups or up to three halogen groups (preferably        fluorine);    -   R_(S) of ULM-g is a C₁-C₆ alkyl group, an optionally substituted        aryl, heteroaryl or heterocycle group or a —(CH₂)_(m)NR₁R₂        group;    -   X and X′ of ULM-g are each independently C═O, C═S, —S(O), S(O)₂,        (preferably X and X′ are both C═O);    -   R^(2′) of ULM-g is an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)alkyl group, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)NR_(1N)R_(2N)        group, an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl,        an optionally substituted        —(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an optionally        substituted —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl or an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(v)NR¹(SO₂)_(w)-Heterocycle, an optionally        substituted —X^(R2′)-alkyl group; an optionally substituted        —X^(R2′)— Aryl group; an optionally substituted —X^(R2′)—        Heteroaryl group; an optionally substituted —X^(R2′)—        Heterocycle group; an optionally substituted;    -   R^(3′) of ULM-g is an optionally substituted alkyl, an        optionally substituted        —(CH₂)_(n)—(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N),        an optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—C(O)NR₁R₂, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle,        an optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(W)—NR₁C(O)R_(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle, an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —O—(CH₂)n-(C═O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —O—(CH₂)n-(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl        or an optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle;        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Aryl group, an optionally        substituted —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heteroaryl        group, an optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heterocycle group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n)-Aryl group, an optionally        substituted —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heteroaryl        group, an optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heterocycle group, an        optionally substituted —X^(R3′)— alkyl group; an optionally        substituted —X^(R3′)— Aryl group; an optionally substituted        —X^(R3′)— Heteroaryl group; an optionally substituted —X^(R3′)—        Heterocycle group; an optionally substituted;    -   R_(1N) and R_(2N) of ULM-g are each independently H, C₁-C₆ alkyl        which is optionally substituted with one or two hydroxyl groups        and up to three halogen groups or an optionally substituted        —(CH₂)_(n)-Aryl, —(CH₂)_(n)-Heteroaryl or —(CH₂)_(n)-Heterocycle        group;    -   V of ULM-g is O, S or NR₁;    -   R₁ of ULM-g is the same as above;    -   R¹ and R_(1′) of ULM-g are each independently H or a C₁-C₃ alkyl        group;    -   X^(R2′) and X^(R3′) of ULM-g are each independently an        optionally substituted —CH₂)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH≡CH—,        —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group, where X_(v) is H, a        halo or a C₁-C₃ alkyl group which is optionally substituted;    -   each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each m′ of ULM-g is independently 0 or 1;    -   each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each n′ of ULM-g is independently 0 or 1;    -   each u of ULM-g is independently 0 or 1;    -   each v of ULM-g is independently 0 or 1;    -   each w of ULM-g is independently 0 or 1; and    -   any one or more of R^(1′), R^(2′), R^(3′), X and X′ of ULM-g is        optionally modified to be covalently bonded to the PTM group        through a linker group when PTM is not ULM′, or when PTM is        ULM′, any one or more of R^(1′), R^(2′), R^(3′), X and X′ of        each of ULM and ULM′ are optionally modified to be covalently        bonded to each other directly or through a linker group, or a        pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof.

In any of the aspects or embodiments described herein, the ULM and whenpresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   each of R^(1′), R^(2′) and R^(3′) of ULM-h are the same as above        and X is C═O, C═S, —S(O) group or a S(O)₂ group, more preferably        a C═O group, and    -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-h are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In any of the aspects or embodiments described herein, the ULM, and whenpresent, ULM′, are each independently according to the chemicalstructure:

wherein:

-   -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-I are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In further preferred aspects of the disclosure, R^(1′) of ULM-g throughULM-i is preferably a hydroxyl group or a group which may be metabolizedto a hydroxyl or carboxylic group, such that the compound represents aprodrug form of an active compound. Exemplary preferred R^(1′) groupsinclude, for example, —(CH₂)_(n)OH, (CH₂)_(n)—O—(C₁-C₆)alkyl group,—(CH₂)_(n)COOH, —(CH₂O)_(n)H, an optionally substituted—(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), or an optionally substituted—(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), wherein n is 0 or 1. Where R^(1′) is orcontains a carboxylic acid group, a hydroxyl group or an amine group,the hydroxyl group, carboxylic acid group or amine (each of which may beoptionally substituted), may be further chemically modified to provide acovalent link to a linker group to which the PTM group (including a ULM′group) is bonded;

X and X′, where present, of ULM-g and ULM-h are preferably a C═O, C═S,—S(O) group or a S(O)₂ group, more preferably a C═O group;

R^(2′) of ULM-g through ULM-i is preferably an optionally substituted—NR¹-T-Aryl, an optionally substituted —NR¹-T-Heteroaryl group or anoptionally substituted —NR¹-T-Heterocycle, where R¹ is H or CH₃,preferably H and T is an optionally substituted —(CH₂)_(n)— group,wherein each one of the methylene groups may be optionally substitutedwith one or two substituents, preferably selected from halogen, an aminoacid sidechain as otherwise described herein or a C₁-C₃ alkyl group,preferably one or two methyl groups, which may be optionallysubstituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1.Alternatively, T may also be a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group,a —(CH₂CH₂O)_(n)— group, a —(OCH₂CH₂)_(n)— group, all of which groupsare optionally substituted.

Preferred Aryl groups for R^(2′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is optionally connected toa PTM group (including a ULM′ group) via a linker group and/oroptionally substituted with a halogen (preferably F or Cl), an amine,monoalkyl- or dialkyl amine (preferably, dimethylamine), F, Cl, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is optionally connected to a PTM group,including a ULM′ group, via a linker group), and/or optionallysubstituted with at least one of F, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃,NO₂, or CN group (in ortho-, meta- and/or para-positions of the phenylring, preferably para-), a naphthyl group, which may be optionallysubstituted, an optionally substituted heteroaryl, preferably anoptionally substituted isoxazole including a methylsubstitutedisoxazole, an optionally substituted oxazole including amethylsubstituted oxazole, an optionally substituted thiazole includinga methyl substituted thiazole, an optionally substituted isothiazoleincluding a methyl substituted isothiazole, an optionally substitutedpyrrole including a methylsubstituted pyrrole, an optionally substitutedimidazole including a methylimidazole, an optionally substitutedbenzimidazole or methoxybenzylimidazole, an optionally substitutedoximidazole or methyloximidazole, an optionally substituted diazolegroup, including a methyldiazole group, an optionally substitutedtriazole group, including a methylsubstituted triazole group, anoptionally substituted pyridine group, including a halo- (preferably, F)or methylsubstitutedpyridine group or an oxapyridine group (where thepyridine group is linked to the phenyl group by an oxygen), anoptionally substituted furan, an optionally substituted benzofuran, anoptionally substituted dihydrobenzofuran, an optionally substitutedindole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), anoptionally substituted quinoline, an optionally substituted groupaccording to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl) each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted phenyl group, an optionally substituted heteroaryl,        or an optionally substituted heterocycle, preferably for example        piperidine, morpholine, pyrrolidine, tetrahydrofuran);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2 of ULM-g through ULM-i) are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1), or an optionally substituted        heterocycle, preferably tetrahydrofuran, tetrahydrothiene,        piperidine, piperazine or morpholine (each of which groups when        substituted, are preferably substituted with a methyl or halo        (F, Br, Cl), each of which groups may be optionally connected to        a PTM group (including a ULM′ group) via a linker group.

In certain preferred aspects,

of ULM-g through ULM-i is a

group,where R^(PRO) and n of ULM-g through ULM-i are the same as above.

Preferred heteroaryl groups for R^(2′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole, an optionally substitutedindolizine, an optionally substituted azaindolizine, an optionallysubstituted benzofuran, including an optionally substituted benzofuran,an optionally substituted isoxazole, an optionally substituted thiazole,an optionally substituted isothiazole, an optionally substitutedthiophene, an optionally substituted pyridine (2-, 3, or 4-pyridine), anoptionally substituted imidazole, an optionally substituted pyrrole, anoptionally substituted diazole, an optionally substituted triazole, atetrazole, an optionally substituted oximidazole, or a group accordingto the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) of ULM-g through ULM-i is H or a C₁-C₆        alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl), each        of which groups may be optionally connected to a PTM group        (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R^(2′) of ULM-g through ULM-i includetetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine,piperazine, pyrrollidine, morpholine, oxane or thiane, each of whichgroups may be optionally substituted, or a group according to thechemical structure:

-   -    preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (often 0 or 1), each of which groups may be optionally        connected to a PTM group (including a ULM′ group) via a linker        group.

Preferred R^(2′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(2′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the figures which areattached hereto). Each of these R^(2′) substituents may be used inconjunction with any number of R^(3′) substituents which are alsodisclosed herein.

R^(3′) of ULM-g through ULM-i is preferably an optionally substituted-T-Aryl, an optionally substituted-T-Heteroaryl, an optionallysubstituted -T-Heterocycle, an optionally substituted-NR¹-T-Aryl, anoptionally substituted —NR¹-T-Heteroaryl or an optionallysubstituted-NR¹-T-Heterocycle, where R¹ is H or a C₁-C₃ alkyl group,preferably H or CH₃, T is an optionally substituted —(CH₂)_(n)— group,wherein each one of the methylene groups may be optionally substitutedwith one or two substituents, preferably selected from halogen, a C₁-C₃alkyl group or the sidechain of an amino acid as otherwise describedherein, preferably methyl, which may be optionally substituted; and n is0 to 6, often 0, 1, 2, or 3 preferably 0 or 1. Alternatively, T may alsobe a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group, a —(CH₂CH₂O)_(n)— group,a —(OCH₂CH₂)_(n)— group, each of which groups is optionally substituted.

Preferred aryl groups for R^(3′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is optionally connected toa PTM group (including a ULM′ group) via a linker group and/oroptionally substituted with at least one of a halogen (preferably F orCl), an amine, monoalkyl- or dialkyl amine (preferably, dimethylamine),an amido group (preferably a —(CH₂)_(m)—NR1C(O)R₂ group where m, R₁ andR₂ are the same as above), a halo (often F or Cl), OH, CH₃, CF₃, OMe,OCF₃, NO₂, CN or a S(O)₂R_(S) group (R_(S) is a a C₁-C₆ alkyl group, anoptionally substituted aryl, heteroaryl or heterocycle group or a—(CH₂)_(m)NR₁R₂ group), each of which may be substituted in ortho-,meta- and/or para-positions of the phenyl ring, preferably para-), or anAryl (preferably phenyl), Heteroaryl or Heterocycle. Preferably saidsubstituent phenyl group is an optionally substituted phenyl group(i.e., the substituent phenyl group itself is preferably substitutedwith at least one of F, Cl, OH, SH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, CNor a linker group to which is attached to a PTM group (including a ULM′group), wherein the substitution occurs in ortho-, meta- and/orpara-positions of the phenyl ring, preferably para-), a naphthyl group,which may be optionally substituted including as described above, anoptionally substituted heteroaryl (preferably an optionally substitutedisoxazole including a methylsubstituted isoxazole, an optionallysubstituted oxazole including a methylsubstituted oxazole, an optionallysubstituted thiazole including a methyl substituted thiazole, anoptionally substituted pyrrole including a methylsubstituted pyrrole, anoptionally substituted imidazole including a methylimidazole, abenzylimidazole or methoxybenzylimidazole, an oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methylsubstituted triazole group, a pyridine group, including a halo-(preferably, F) or methylsubstitutedpyridine group or an oxapyridinegroup (where the pyridine group is linked to the phenyl group by anoxygen) or an optionally substituted heterocycle (tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine,tetrahydroquinoline, oxane or thiane. Each of the aryl, heteroaryl orheterocyclic groups may be optionally connected to a PTM group(including a ULM′ group) via a linker group.

Preferred Heteroaryl groups for R^(3′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl). Each        of said heteroaryl groups may be optionally connected to a PTM        group (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R³ of ULM-g through ULM-i includetetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine,tetrahydrofuran, tetrahydrothiophene, oxane and thiane, each of whichgroups may be optionally substituted or a group according to thechemical structure:

preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6        (preferably 0 or 1), wherein each of said Heterocycle groups may        be optionally connected to a PTM group (including a ULM′ group)        via a linker group.

Preferred R^(3′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(3′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the figures which areattached hereto). Each of these R^(3′) substituents may be used inconjunction with any number of R^(2′) substituents, which are alsodisclosed herein.

In certain alternative preferred embodiments, R^(2′) of ULM-g throughULM-i is an optionally substituted —NR₁—X^(R2′)-alkyl group,—NR₁—X^(R2′)-Aryl group; an optionally substituted —NR₁— X^(R2′)-HET, anoptionally substituted —NR₁—X^(R2′)-Aryl-HET or an optionallysubstituted —NR₁— X^(R2′)-HET-Aryl,

wherein:

-   -   R₁ of ULM-g through ULM-i is H or a C₁-C₃ alkyl group        (preferably H);    -   X^(R2′) of ULM-g through ULM-i is an optionally substituted        —CH₂)_(n)—, —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans),        —(CH₂)_(n)—CH≡CH—, —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group;        and    -   X_(v) of ULM-g through ULM-i is H, a halo or a C₁-C₃ alkyl group        which is optionally substituted with one or two hydroxyl groups        or up to three halogen groups;    -   Alkyl of ULM-g through ULM-i is an optionally substituted C₁-C₁₀        alkyl (preferably a C₁-C₆ alkyl) group (in certain preferred        embodiments, the alkyl group is end-capped with a halo group,        often a Cl or Br);    -   Aryl of ULM-g through ULM-i is an optionally substituted phenyl        or naphthyl group (preferably, a phenyl group); and    -   HET of ULM-g through ULM-i is an optionally substituted oxazole,        isoxazole, thiazole, isothiazole, imidazole, diazole,        oximidazole, pyrrole, pyrollidine, furan, dihydrofuran,        tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,        pyridine, piperidine, piperazine, morpholine, benzofuran,        indole, indolizine, azaindolizine, quinoline (when substituted,        each preferably substituted with a C₁-C₃ alkyl group, preferably        methyl or a halo group, preferably F or Cl) or a group according        to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1).

Each of said groups may be optionally connected to a PTM group(including a ULM′ group) via a linker group.

In certain alternative preferred embodiments of the present disclosure,R^(3′) of ULM-g through ULM-i is an optionally substituted—(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)—R^(S3′) group, an optionallysubstituted-(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)—R^(S3′) group, anoptionally substituted —X^(R3′)-alkyl group, an optionally substituted—X^(R3′)-Aryl group; an optionally substituted —X^(R3′)-HET group, anoptionally substituted —X^(R3′)-Aryl-HET group or an optionallysubstituted —X^(R3′)-HET-Aryl group,

wherein:

-   -   R^(S3′) is an optionally substituted alkyl group (C₁-C₁₀,        preferably C₁-C₆ alkyl), an optionally substituted Aryl group or        a HET group;    -   R_(1′) is H or a C₁-C₃ alkyl group (preferably H);    -   V is O, S or NR_(1′);    -   X^(R3′) is —(CH₂)_(n)—, —(CH₂CH₂O)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH≡CH—,        or a C₃-C₆ cycloalkyl group, all optionally substituted;    -   X_(v) is H, a halo or a C₁-C₃ alkyl group which is optionally        substituted with one or two hydroxyl groups or up to three        halogen groups;    -   Alkyl is an optionally substituted C₁-C₁₀ alkyl (preferably a        C₁-C₆ alkyl) group (in certain preferred embodiments, the alkyl        group is end-capped with a halo group, often a Cl or Br);    -   Aryl is an optionally substituted phenyl or napthyl group        (preferably, a phenyl group); and    -   HET is an optionally substituted oxazole, isoxazole, thiazole,        isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, benzofuran, indole, indolizine,        azaindolizine, quinoline (when substituted, each preferably        substituted with a C₁-C₃ alkyl group, preferably methyl or a        halo group, preferably F or Cl), or a group according to the        chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1);    -   each m′ of ULM-g through ULM-i is 0 or 1; and    -   each n′ of ULM-g through ULM-i is 0 or 1;    -   wherein each of said compounds, preferably on the alkyl, Aryl or        Het groups, is optionally connected to a PTM group (including a        ULM′ group) via a linker group.

In alternative embodiments, R³′ of ULM-g through ULM-i is—(CH₂)_(n)-Aryl, —(CH₂CH₂O)_(n)-Aryl, —(CH₂)_(n)-HET or—(CH₂CH₂O)_(n)-HET, wherein:

-   -   said Aryl of ULM-g through ULM-i is phenyl which is optionally        substituted with one or two substitutents, wherein said        substituent(s) is preferably selected from —(CH₂)_(n)OH, C₁-C₆        alkyl which itself is further optionally substituted with CN,        halo (up to three halo groups), OH, —(CH₂)_(n)O(C₁-C₆)alkyl,        amine, mono- or di-(C₁-C₆ alkyl) amine wherein the alkyl group        on the amine is optionally substituted with 1 or 2 hydroxyl        groups or up to three halo (preferably F, Cl) groups, or    -   said Aryl group of ULM-g through ULM-i is substituted with        —(CH₂)_(n)OH, —(CH₂)_(n)—O—(C₁-C₆)alkyl,        —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl, —(CH₂)_(n)—C(O)(C₀-C₆)        alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,        —(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl)        amine wherein the alkyl group on the amine is optionally        substituted with 1 or 2 hydroxyl groups or up to three halo        (preferably F, Cl) groups, CN, NO₂, an optionally substituted        —(CH₂)_(n)—(V)_(m′)—CH₂)_(n)—(V)_(m′)—(C₁-C₆)alkyl group, a        —(V)_(m′)—(CH₂CH₂O)_(n)—R^(PEG) group where V is O, S or        NR_(1′), R_(1′) is H or a C₁-C₃ alkyl group (preferably H) and        R^(PEG) is H or a C₁-C₆ alkyl group which is optionally        substituted (including being optionally substituted with a        carboxyl group), or    -   said Aryl group of ULM-g through ULM-i is optionally substituted        with a heterocycle, including a heteroaryl, selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, benzofuran, indole, indolizine, azaindolizine, (when        substituted each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   HET of ULM-g through ULM-i is preferably oxazole, isoxazole,        thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, quinoline, (each preferably substituted        with a C₁-C₃ alkyl group, preferably methyl or a halo group,        preferably F or Cl), benzofuran, indole, indolizine,        azaindolizine, or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each m′ of ULM-g through ULM-i is independently 0 or 1; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1),    -   wherein each of said compounds, preferably on said Aryl or HET        groups, is optionally connected to a PTM group (including a ULM′        group) via a linker group.

In still additional embodiments, preferred compounds include thoseaccording to the chemical structure:

wherein:

-   -   R^(1′) of ULM-i is OH or a group which is metabolized in a        patient or subject to OH;    -   R^(2′) of ULM-i is a —NH—CH₂-Aryl-HET (preferably, a phenyl        linked directly to a methyl substituted thiazole);    -   R^(3′) of ULM-i is a —CHR^(CR3′)—NH—C(O)—R^(3P1) group or a        —CHR^(CR3′)—R^(3P2) group;    -   R^(CR3′) of ULM-i is a C₁-C₄ alkyl group, preferably methyl,        isopropyl or tert-butyl;    -   R^(3P1) of ULM-i is C₁-C₃ alkyl (preferably methyl), an        optionally substituted oxetane group (preferably methyl        substituted, a —(CH₂)_(n)OCH₃ group where n is 1 or 2        (preferably 2), or a

group (the ethyl ether group is preferably meta-substituted on thephenyl moiety), a morpholino group (linked to the carbonyl at the 2- or3-position;

-   -   R^(3P2) of ULM-i is a

group;

-   -   Aryl of ULM-i is phenyl;    -   HET of ULM-i is an optionally substituted thiazole or        isothiazole; and    -   R^(HET) of ULM-i is H or a halo group (preferably H);    -   or a pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof, wherein each of said compounds is optionally        connected to a PTM group (including a ULM′ group) via a linker        group.

In certain aspects, bifunctional compounds comprising a ubiquitin E3ligase binding moiety (ULM), wherein ULM is a group according to thechemical structure:

wherein:each R₅ and R₆ of ULM-j is independently OH, SH, or optionallysubstituted alkyl or R₅, R₆, and the carbon atom to which they areattached form a carbonyl;R₇ of ULM-j is H or optionally substituted alkyl;E of ULM-j is a bond, C═O, or C═S;G of ULM-j is a bond, optionally substituted alkyl, —COOH or C═J;

J of ULM-j is 0 or N—R₈;

R₈ of ULM-j is H, CN, optionally substituted alkyl or optionallysubstituted alkoxy;M of ULM-j is optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclic or

each R₉ and R₁₀ of ULM-j is independently H; optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedhydroxyalkyl, optionally substituted thioalkyl, a disulphide linked ULM,optionally substituted heteroaryl, or haloalkyl; or R₉, R₁₀, and thecarbon atom to which they are attached form an optionally substitutedcycloalkyl;R₁₁ of ULM-j is optionally substituted heterocyclic, optionallysubstituted alkoxy, optionally substituted heteroaryl, optionallysubstituted aryl, or

R₁₂ of ULM-j is H or optionally substituted alkyl;R₁₃ of ULM-j is H, optionally substituted alkyl, optionally substitutedalkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl,optionally substituted aralkylcarbonyl, optionally substitutedarylcarbonyl, optionally substituted (heterocyclyl)carbonyl, oroptionally substituted aralkyl; optionally substituted(oxoalkyl)carbamate,each R₁₄ of ULM-j is independently H, haloalkyl, optionally substitutedcycloalkyl, optionally substituted alkyl or optionally substitutedheterocycloalkyl;R₁₅ of ULM-j is H, optionally substituted heteroaryl, haloalkyl,optionally substituted aryl, optionally substituted alkoxy, oroptionally substituted heterocyclyl;each R₁₆ of ULM-j is independently halo, optionally substituted alkyl,optionally substituted haloalkyl, CN, or optionally substitutedhaloalkoxy;each R₂₅ of ULM-j is independently H or optionally substituted alkyl; orboth R₂₅ groups can be taken together to form an oxo or optionallysubstituted cycloalkyl group;

R₂₃ of ULM-j is H or OH;

Z₁, Z₂, Z₃, and Z₄ of ULM-j are independently C or N; ando of ULM-j is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt,stereoisomer, solvate or polymorph thereof.

In certain embodiments, wherein G of ULM-j is C═J, J is O, R₇ is H, eachR₁₄ is H, and o is 0.

In certain embodiments, wherein G of ULM-j is C═J, J is O, R₇ is H, eachR₁₄ is H, R₁₅ is optionally substituted heteroaryl, and o is 0. In otherinstances, E is C═O and M is

In certain embodiments, wherein E of ULM-j is C═O, R₁₁ is optionallysubstituted heterocyclic or

and M is

In certain embodiments, wherein E of ULM-j is C═O, M is

and R₁₁ is

each R₁₈ is independently halo, optionally substituted alkoxy, cyano,optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1,2, 3, or 4.

In certain embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C═J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is 0;    -   R₁₅ of ULM-k is

and

-   -   R₁₇ of ULM-k is H, halo, optionally substituted cycloalkyl,        optionally substituted alkyl, optionally substituted alkenyl,        and haloalkyl.

In other instances, R₁₇ of ULM-k is alkyl (e.g., methyl) or cycloalkyl(e.g., cyclopropyl).

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

G of ULM-k is C═J, J is O;

R₇ of ULM-k is H;

each R₁₄ of ULM-k is H;

o of ULM-k is 0; and

R₁₅ of ULM-k is selected from the group consisting of:

wherein R₃₀ of ULM-k is H or an optionally substituted alkyl.

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

E of ULM-k is C═O;

M of ULM-k is

and

R₁₁ of ULM-k is selected from the group consisting of:

In still other embodiments, a compound of the chemical structure,

wherein E of ULM-k is C═O;

R₁₁ of ULM-k is

and

M of ULM-k is

q of ULM-k is 1 or 2;

R₂₀ of ULM-k is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, or

R₂₁ of ULM-k is H or optionally substituted alkyl; andR₂₂ of ULM-k is H, optionally substituted alkyl, optionally substitutedalkoxy, or haloalkyl.

In any embodiment described herein, R₁₁ of ULM-j or ULM-k is selectedfrom the group consisting of:

In certain embodiments, R₁₁ of ULM-j or ULM-k is selected from the groupconsisting of:

In certain embodiments, ULM (or when present ULM′) is a group accordingto the chemical structure:

wherein:

-   -   X of ULM-1 is O or S;    -   Y of ULM-1 is H, methyl or ethyl;    -   R₁₇ of ULM-1 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;    -   M of ULM-1 is optionally substituted aryl, optionally        substituted heteroaryl, or

-   -   R₉ of ULM-1 is H;    -   R₁₀ of ULM-1 is H, optionally substituted alkyl, optionally        substituted haloalkyl, optionally substituted heteroaryl,        optionally substituted aryl, optionally substituted        hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;    -   R₁₁ of ULM-1 is optionally substituted heteroaromatic,        optionally substituted heterocyclic, optionally substituted aryl        or

-   -   R₁₂ of ULM-1 is H or optionally substituted alkyl; and    -   R₁₃ of ULM-1 is H, optionally substituted alkyl, optionally        substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl; optionally substituted (oxoalkyl)carbamate.

In some embodiments, ULM and where present, ULM′, are each independentlya group according to the chemical structure:

wherein:

-   -   Y of ULM-m is H, methyol or ethyl    -   R₉ of ULM-m is H;    -   R₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or        cyclohexyl;    -   R₁₁ of ULM-m is optionally substituted amide, optionally        substituted isoindolinone, optionally substituted isooxazole,        optionally substituted heterocycles.

In other proffered embodiments of the disclosure, ULM and where present,ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R₁₇ of ULM-n is methyl, ethyl, or cyclopropyl; and    -   R₉, R₁₀, and R₁₁ of ULM-n are as defined above. In other        instances, R₉ is H; and    -   R₁₀ of ULM-n is H, alkyl, or cycloalkyl (preferably, isopropyl,        tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

In any of the aspects or embodiments described herein, the ULM (or whenpresent, ULM′) as described herein may be a pharmaceutically acceptablesalt, enantiomer, diastereomer, solvate or polymorph thereof. Inaddition, in any of the aspects or embodiments described herein, the ULM(or when present, ULM′) as described herein may be coupled to a PTMdirectly via a bond or by a chemical linker.

In certain aspects of the disclosure, the ULM moiety is selected fromthe group consisting of:

wherein the VLM may be connected to a PTM via a linker, as describedherein, at any appropriate location, including, e.g., an aryl,heteroaryl, phenyl, or phenyl of an indole group, optionally via anyappropriate functional group, such as an amine, ester, ether, alkyl, oralkoxy.

Exemplary Linkers

In certain embodiments, the compounds as described herein include one ormore PTMs chemically linked or coupled to one or more ULMs (e.g., atleast one of CLM, VLM, MLM, ILM, or a combination thereof) via achemical linker (L). In certain embodiments, the linker group L is agroup comprising one or more covalently connected structural units(e.g., -A^(L) ₁ . . . (A^(L))_(q)- or -(A^(L))_(q)-), wherein A^(L) ₁ isa group coupled to PTM, and (A^(L))_(q) is a group coupled to ULM.

In certain embodiments, the linker group L is -(A^(L))_(q)-:

-   -   (A^(L))_(q) is a group which is connected to at least one of a        ULM (such as a VLM, VLM′, CLM, CLM′, ILM, ILM′, MLM, and/or        MLM′), a PTM (such as a PTM and PTM′), or a combination thereof;        and    -   q of the linker is an integer greater than or equal to 1;    -   each A^(L) is independently selected from the group consisting        of, a bond, CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3),        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₅₋₁₃ spirocycloalkyl optionally substituted with        0-9 R^(L1) and/or R^(L2) groups, C₃₋₁₁heterocyclyl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, C₅₋₁₃        spiroheterocycloalkyl optionally substituted with 0-8 R^(L1)        and/or R^(L2) groups, aryl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, heteroaryl optionally substituted        with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1) or R^(L2),        each independently are optionally linked to other groups to form        cycloalkyl and/or heterocyclyl moiety, optionally substituted        with 0-4 R^(L5) groups; and    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In certain embodiments, q of the linker is an integer greater than orequal to 0. In certain embodiments, q is an integer greater than orequal to 1.

In certain embodiments, e.g., where q of the linker is greater than 2,(A^(L))_(q) is a group which is connected to ULM, and A^(L) ₁ and(A^(L))_(q) are connected via structural units of the linker (L).

In certain embodiments, e.g., where q of the linker is 2, (A^(L))_(q) isa group which is connected to A^(L) ₁ and to a ULM.

In certain embodiments, e.g., where q of the linker is 1, the structureof the linker group L is -A^(L) ₁-, and A^(L) ₁ is a group which isconnected to a ULM moiety and a PTM moiety.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

-   -   —NR(CH₂)_(n)-(lower alkyl)-, —NR(CH₂)_(n)-(lower alkoxyl)-,        —NR(CH₂)_(n)-(lower alkoxyl)-OCH₂—, —NR(CH₂)_(n)-(lower        alkoxyl)-(lower alkyl)-OCH₂—, —NR(CH₂)_(n)-(cycloalkyl)-(lower        alkyl)-OCH₂—, —NR(CH₂)_(n)-(hetero cycloalkyl)-,        —NR(CH₂CH₂O)_(n)-(lower alkyl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(hetero        cycloalkyl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-Aryl-O—CH₂—,        —NR(CH₂CH₂O)_(n)-(hetero aryl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(cyclo        alkyl)-O-(hetero aryl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(cyclo        alkyl)-O-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(lower        alkyl)-NH-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(lower        alkyl)-O-Aryl-CH₂, —NR(CH₂CH₂O)_(n)-cycloalkyl-O-Aryl-,        —NR(CH₂CH₂O)_(n)-cycloalkyl-O-(heteroaryl)l-, —NR(CH₂CH₂)_(n)—        (cycloalkyl)-O-(heterocycle)-CH₂,        —NR(CH₂CH₂)_(n)-(heterocycle)-(heterocycle)-CH₂,        —N(R1R2)-(heterocycle)-CH₂; where        -   n of the linker can be 0 to 10;        -   R of the linker can be H, lower alkyl;        -   R1 and R2 of the linker can form a ring with the connecting            N.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

-   -   —N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,    -   —O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,    -   —O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;    -   —N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;    -   —(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;    -   —(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-;

wherein

m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

when the number is zero, there is no N—O or O—O bond

R of the linker is H, methyl and ethyl;

X of the linker is H and F

where m of the linker can be 2, 3, 4, 5

wherein each n and m of the linker can independently be 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m, n, o, p, q, or r is independently 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, L is selected from thegroup consisting of:

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with R^(Q), each        R^(Q) is independently a H, halo, OH, CN, CF₃, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 4-8        membered ring system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C₁-C₆ alkoxy (linear, branched,        optionally substituted); and    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with R^(Q), each R^(Q) is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with 0; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker group is optionally substituted(poly)ethyleneglycol having between 1 and about 100 ethylene glycolunits, between about 1 and about 50 ethylene glycol units, between 1 andabout 25 ethylene glycol units, between about 1 and 10 ethylene glycolunits, between 1 and about 8 ethylene glycol units and 1 and 6 ethyleneglycol units, between 2 and 4 ethylene glycol units, or optionallysubstituted alkyl groups interdispersed with optionally substituted, O,N, S, P or Si atoms. In certain embodiments, the linker is substitutedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the linker may be asymmetric or symmetrical.

In any of the embodiments of the compounds described herein, the linkergroup may be any suitable moiety as described herein. In one embodiment,the linker is a substituted or unsubstituted polyethylene glycol groupranging in size from about 1 to about 12 ethylene glycol units, between1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycolunits, between about 2 and 5 ethylene glycol units, between about 2 and4 ethylene glycol units.

In another embodiment, the present disclosure is directed to a compoundwhich comprises a PTM group as described above, which binds to a targetprotein or polypeptide (e.g., Estrogen Receptor), which is ubiquitinatedby an ubiquitin ligase and is chemically linked directly to the ULMgroup or through a linker moiety L, or PTM is alternatively a ULM′ groupwhich is also a ubiquitin ligase binding moiety, which may be the sameor different than the ULM group as described above and is linkeddirectly to the ULM group directly or through the linker moiety; and Lis a linker moiety as described above which may be present or absent andwhich chemically (covalently) links ULM to PTM, or a pharmaceuticallyacceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

In certain embodiments, the linker group L is a group comprising one ormore covalently connected structural units independently selected fromthe group consisting of:

The X is selected from the group consisting of O, N, S, S(O) and SO₂; nis integer from 1 to 5;R^(L1) is hydrogen or alkyl,

is a mono- or bicyclic aryl or heteroaryl optionally substituted with1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy,alkoxy or cyano;

is a mono- or bicyclic cycloalkyl or a heterocycloalkyl optionallysubstituted with 1-3 substituents selected from alkyl, halogen,haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring fragment can beoptionally substituted with 1, 2 or 3 substituents selected from thegroup consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy andcyano. In an embodiment, the linker group L comprises up to 10covalently connected structural units, as described above.

Although the ULM group and PTM group may be covalently linked to thelinker group through any group which is appropriate and stable to thechemistry of the linker, in preferred aspects of the present disclosure,the linker is independently covalently bonded to the ULM group and thePTM group preferably through an amide, ester, thioester, keto group,carbamate (urethane), carbon or ether, each of which groups may beinserted anywhere on the ULM group and PTM group to provide maximumbinding of the ULM group on the ubiquitin ligase and the PTM group onthe target protein to be degraded. (It is noted that in certain aspectswhere the PTM group is a ULM group, the target protein for degradationmay be the ubiquitin ligase itself). In certain preferred aspects, thelinker may be linked to an optionally substituted alkyl, alkylene,alkene or alkyne group, an aryl group or a heterocyclic group on the ULMand/or PTM groups.

Exemplary PTMs

In preferred aspects of the disclosure, the PTM group is a group, whichbinds to target proteins. Targets of the PTM group are numerous in kindand are selected from proteins that are expressed in a cell such that atleast a portion of the sequences is found in the cell and may bind to aPTM group. The term “protein” includes oligopeptides and polypeptidesequences of sufficient length that they can bind to a PTM groupaccording to the present disclosure. Any protein in a eukaryotic systemor a microbial system, including a virus, bacteria or fungus, asotherwise described herein, are targets for ubiquitination mediated bythe compounds according to the present disclosure. Preferably, thetarget protein is a eukaryotic protein.

PTM groups according to the present disclosure include, for example, anymoiety which binds to a protein specifically (binds to a target protein)and includes the following non-limiting examples of small moleculetarget protein moieties: Hsp90 inhibitors, selective estrogen receptormodulators, kinase inhibitors, HDM2 & MDM2 inhibitors, compoundstargeting Human BET Bromodomain-containing proteins, HDAC inhibitors,human lysine methyltransferase inhibitors, angiogenesis inhibitors,nuclear hormone receptor compounds, immunosuppressive compounds, andcompounds targeting the aryl hydrocarbon receptor (AHR), among numerousothers. The compositions described below exemplify some of the membersof small molecule target protein binding moieties. Such small moleculetarget protein binding moieties also include pharmaceutically acceptablesalts, enantiomers, solvates and polymorphs of these compositions, aswell as other small molecules that may target a protein of interest.These binding moieties are linked to the ubiquitin ligase binding moietypreferably through a linker in order to present a target protein (towhich the protein target moiety is bound) in proximity to the ubiquitinligase for ubiquitination and degradation.

Any protein, which can bind to a protein target moiety or PTM group andacted on or degraded by an ubiquitin ligase is a target proteinaccording to the present disclosure. In general, target proteins mayinclude, for example, structural proteins, receptors, enzymes, cellsurface proteins, proteins pertinent to the integrated function of acell, including proteins involved in catalytic activity, aromataseactivity, motor activity, helicase activity, metabolic processes(anabolism and catabolism), antioxidant activity, proteolysis,biosynthesis, proteins with kinase activity, oxidoreductase activity,transferase activity, hydrolase activity, lyase activity, isomeraseactivity, ligase activity, enzyme regulator activity, signal transduceractivity, structural molecule activity, binding activity (protein, lipidcarbohydrate), receptor activity, cell motility, membrane fusion, cellcommunication, regulation of biological processes, development, celldifferentiation, response to stimulus, behavioral proteins, celladhesion proteins, proteins involved in cell death, proteins involved intransport (including protein transporter activity, nuclear transport,ion transporter activity, channel transporter activity, carrieractivity, permease activity, secretion activity, electron transporteractivity, pathogenesis, chaperone regulator activity, nucleic acidbinding activity, transcription regulator activity, extracellularorganization and biogenesis activity, translation regulator activity.Proteins of interest can include proteins from eukaryotes andprokaryotes including humans as targets for drug therapy, other animals,including domesticated animals, microbials for the determination oftargets for antibiotics and other antimicrobials and plants, and evenviruses, among numerous others.

The present disclosure may be used to treat a number of disease statesand/or conditions, including any disease state and/or condition in whichproteins are dysregulated and where a patient would benefit from thedegradation and/or inhibition of proteins.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,additive or excipient, and optionally an additional bioactive agent. Thetherapeutic compositions modulate protein degradation and/or inhibitionin a patient or subject, for example, an animal such as a human, and canbe used for treating or ameliorating disease states or conditions whichare modulated through the degraded/inhibited protein. In certainembodiments, the therapeutic compositions as described herein may beused to effectuate the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer. In certainadditional embodiments, the disease is at least one of breast cancer,uterine cancer, ovarian cancer, prostate cancer, endometrial cancer,endometriosis, or a combination thereof.

In alternative aspects, the present disclosure relates to a method fortreating a disease state or ameliorating the symptoms of a disease orcondition in a subject in need thereof by degrading a protein orpolypeptide through which a disease state or condition is modulatedcomprising administering to said patient or subject an effective amount,e.g., a therapeutically effective amount, of at least one compound asdescribed hereinabove, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient, and optionally an additionalbioactive agent, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.The method according to the present disclosure may be used to treat alarge number of disease states or conditions including cancer, by virtueof the administration of effective amounts of at least one compounddescribed herein. The disease state or condition may be a disease causedby a microbial agent or other exogenous agent such as a virus, bacteria,fungus, protozoa or other microbe or may be a disease state, which iscaused by overexpression of a protein, which leads to a disease stateand/or condition.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The term “target protein” is used to describe a protein or polypeptide,which is a target for binding to a compound according to the presentdisclosure and degradation by ubiquitin ligase hereunder. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to at least one ULM group(e.g. VHL, CLM, ILM, and/or MLM) through at least one linker group L.

Target proteins, which may be bound to the protein target moiety anddegraded by the ligase to which the ubiquitin ligase binding moiety isbound, include any protein or peptide, including fragments thereof,analogues thereof, and/or homologues thereof. Target proteins includeproteins and peptides having any biological function or activityincluding structural, regulatory, hormonal, enzymatic, genetic,immunological, contractile, storage, transportation, and signaltransduction. More specifically, a number of drug targets for humantherapeutics represent protein targets to which protein target moietymay be bound and incorporated into compounds according to the presentdisclosure. These include proteins which may be used to restore functionin numerous polygenic diseases, including for example B7.1 and B7,TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in theapotosis pathway, C₅a receptor, HMG-CoA reductase, PDE Vphosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII,PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO)synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopaminereceptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase,tryptase serine protease, thymidylate synthase, purine nucleosidephosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonicanhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reversetranscriptase, sodium channel, multi drug resistance (MDR), proteinP-glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinasep56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins andreceptors, inosine monophosphate dehydrogenase, p38 MAP Kinase,RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV,NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I),protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase,cyclin dependent kinases, vascular endothelial growth factor, oxytocinreceptor, microsomal transfer protein inhibitor, bile acid transportinhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycinereceptor, noradrenaline reuptake receptor, endothelin receptors,neuropeptide Y and receptor, estrogen receptor (ER), androgen receptors,adenosine receptors, adenosine kinase and AMP deaminase, purinergicreceptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases,geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid,tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor,Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGFreceptor tyrosine kinase. Additional protein targets include, forexample, ecdysone 20-monooxygenase, ER, ion channel of the GABA gatedchloride channel, acetylcholinesterase, voltage-sensitive sodium channelprotein, calcium release channel, and chloride channels. Still furthertarget proteins include Acetyl-CoA carboxylase, adenylosuccinatesynthetase, protoporphyrinogen oxidase, andenolpyruvylshikimate-phosphate synthase.

These various protein targets may be used in screens that identifycompound moieties which bind to the protein and by incorporation of themoiety into compounds according to the present disclosure, the level ofactivity of the protein may be altered for therapeutic end result.

The term “protein target moiety” or PTM is used to describe a smallmolecule which binds to a target protein or other protein or polypeptideof interest and places/presents that protein or polypeptide in proximityto a ubiquitin ligase, such that degradation of the protein orpolypeptide by ubiquitin ligase may occur. Non-limiting examples ofsmall molecule target protein binding moieties include selectiveestrogen receptor modulators, Hsp90 inhibitors, kinase inhibitors, MDM2inhibitors, compounds targeting Human BET Bromodomain-containingproteins, HDAC inhibitors, human lysine methyltransferase inhibitors,angiogenesis inhibitors, immunosuppressive compounds, and compoundstargeting the aryl hydrocarbon receptor (AHR), among numerous others.The compositions described below exemplify some of the members of thesmall molecule target proteins.

Exemplary protein target moieties according to the present disclosureinclude, haloalkane halogenase inhibitors, selective estrogen receptormodulators, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors,compounds targeting Human BET Bromodomain-containing proteins, HDACinhibitors, human lysine methyltransferase inhibitors, angiogenesisinhibitors, immunosuppressive compounds, and compounds targeting thearyl hydrocarbon receptor (AHR).

The compositions described herein exemplify some of the members of thesetypes of small molecule target protein binding moieties. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. References which are cited herein below are incorporated byreference herein in their entirety.

In any embodiment or aspect described herein, the PTM may be representedby the Formula PTM-I:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   at least one R_(PTM2), each independently selected from H, OH,        halogen, CN, CF₃, SO₂-alkyl, O-lower alkyl;    -   at least one R_(PTM3), each independently selected from H,        halogen;    -   ULM is an E3 ligase binding moiety as described herein; and    -   L is a bond or a linker moiety as described herein.

In any embodiment or aspect described herein, the PTM may be representedby the Formula PTM-I:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   each R_(PTM2) is independently selected from H, OH, halogen, CN,        CF₃, SO₂-alkyl, O-lower alkyl;    -   each R_(PTM3) is independently selected from H, halogen;    -   ULM is an E3 ligase binding moiety as described herein;    -   L is a bond or a linker moiety as described herein;    -   the PTM-I comprises as least one of R_(PTM2), at least one        R_(PTM3), or a combination thereof on the respective rings.

In any embodiment or aspect described herein, PTM-I has at least one of:two R_(PTM2), two R_(PTM3), or a combination thereof.

In any embodiment or aspect described herein, the PTM may be representedby the Formula PTM-II:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   R_(PTM2) and R_(PTM4) are independently selected from H, OH,        halogen, CN, CF₃, SO₂-alkyl, O-lower alkyl;    -   R_(PTM3) and R_(PTM5) are independently selected from H,        halogen;    -   ULM is an E3 ligase binding moiety as described herein; and    -   L is a bond or a linker moiety as described herein.

In certain embodiments, O(CO)R_(PTM) functions as a prodrug of thecorresponding phenol in Formula PTM-I or PTM-II.

In any embodiment or aspect described herein, the O-lower alkyl of PTM-Ior PTM-II an alkyl chain with carbon number 1 to 3.

Therapeutic Compositions

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one bifunctional compound as described herein, andone or more of the compounds otherwise described herein, all ineffective amounts, in combination with a pharmaceutically effectiveamount of a carrier, additive or excipient, represents a further aspectof the present disclosure.

The present disclosure includes, where applicable, the compositionscomprising the pharmaceutically acceptable salts, in particular, acid orbase addition salts of compounds as described herein. The acids whichare used to prepare the pharmaceutically acceptable acid addition saltsof the aforementioned base compounds useful according to this aspect arethose which form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3naphthoate)]salts, among numerous others.

Pharmaceutically acceptable base addition salts may also be used toproduce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform non-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (eg, calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

The compounds as described herein may, in accordance with thedisclosure, be administered in single or divided doses by the oral,parenteral or topical routes. Administration of the active compound mayrange from continuous (intravenous drip) to several oral administrationsper day (for example, Q.I.D.) and may include oral, topical, parenteral,intramuscular, intravenous, sub-cutaneous, transdermal (which mayinclude a penetration enhancement agent), buccal, sublingual andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon the pharmacokinetics of theparticular agent chosen as well as the severity of disease in thepatient. Administration of compounds according to the present disclosureas sprays, mists, or aerosols for intra-nasal, intra-tracheal orpulmonary administration may also be used. The present disclosuretherefore also is directed to pharmaceutical compositions comprising aneffective amount of compound as described herein, optionally incombination with a pharmaceutically acceptable carrier, additive orexcipient. Compounds according to the present disclosure may beadministered in immediate release, intermediate release or sustained orcontrolled release forms. Sustained or controlled release forms arepreferably administered orally, but also in suppository and transdermalor other topical forms. Intramuscular injections in liposomal form mayalso be used to control or sustain the release of compound at aninjection site.

The compositions as described herein may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers and mayalso be administered in controlled-release formulations.Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions as described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions as described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions as described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions as described herein maybe administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions as described herein may also beadministered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this disclosure include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. In certain preferred aspects of the disclosure, the compounds maybe coated onto a stent which is to be surgically implanted into apatient in order to inhibit or reduce the likelihood of occlusionoccurring in the stent in the patient.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions as described herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition as describedherein that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Preferably, thecompositions should be formulated to contain between about 0.05milligram to about 750 milligrams or more, more preferably about 1milligram to about 600 milligrams, and even more preferably about 10milligrams to about 500 milligrams of active ingredient, alone or incombination with at least one other compound according to the presentdisclosure.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject in need of therapy using compounds according to themethods described herein can be treated by administering to the patient(subject) an effective amount of the compound according to the presentdisclosure including pharmaceutically acceptable salts, solvates orpolymorphs, thereof optionally in a pharmaceutically acceptable carrieror diluent, either alone, or in combination with other known therapeuticagents as otherwise identified herein.

These compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, including transdermally, in liquid, cream,gel, or solid form, or by aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such asanti-cancer agents, among others. In certain preferred aspects of thedisclosure, one or more compounds according to the present disclosureare coadministered with another bioactive agent, such as an anti-canceragent or a would healing agent, including an antibiotic, as otherwisedescribed herein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound are then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Therapeutic Methods

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including cancer, which may be treated using compounds according to thepresent disclosure are set forth hereinabove.

The description provides therapeutic compositions as described hereinfor effectuating the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer. In certainadditional embodiments, the disease is breast cancer, uterine cancer,ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or acombination thereof. As such, in another aspect, the descriptionprovides a method of ubiquitinating/degrading a target protein in acell. In certain embodiments, the method comprises administering abifunctional compound as described herein comprising, e.g., a ULM and aPTM, preferably linked through a linker moiety, as otherwise describedherein, wherein the ULM is coupled to the PTM and wherein the ULMrecognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, suchas an E3 ubiquitin ligase including cereblon, VHL, IAP, and/or MDM2) andthe PTM recognizes the target protein such that degradation of thetarget protein will occur when the target protein is placed in proximityto the ubiquitin ligase, thus resulting in degradation/inhibition of theeffects of the target protein and the control of protein levels. Thecontrol of protein levels afforded by the present disclosure providestreatment of a disease state or condition, which is modulated throughthe target protein by lowering the level of that protein in the cell,e.g., cell of a patient. In certain embodiments, the method comprisesadministering an effective amount of a compound as described herein,optionally including a pharmaceutically acceptable excipient, carrier,adjuvant, another bioactive agent or combination thereof.

In additional embodiments, the description provides methods for treatingor ameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptableexcipient, carrier, adjuvant, another bioactive agent or combinationthereof, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

In another embodiment, the present disclosure is directed to a method oftreating a human patient in need for a disease state or conditionmodulated through a protein where the degradation of that protein willproduce a therapeutic effect in the patient, the method comprisingadministering to a patient in need an effective amount of a compoundaccording to the present disclosure, optionally in combination withanother bioactive agent. The disease state or condition may be a diseasecaused by a microbial agent or other exogenous agent such as a virus,bacteria, fungus, protozoa or other microbe or may be a disease state,which is caused by overexpression of a protein, which leads to a diseasestate and/or condition

The term “disease state or condition” is used to describe any diseasestate or condition wherein protein dysregulation (i.e., the amount ofprotein expressed in a patient is elevated) occurs and where degradationof one or more proteins in a patient may provide beneficial therapy orrelief of symptoms to a patient in need thereof. In certain instances,the disease state or condition may be cured.

Disease states or conditions which may be treated using compoundsaccording to the present disclosure include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachsdisease, Turner syndrome.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present disclosure include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present disclosure, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, antiviral agents, especially including anti-HIV agents andanti-HCV agents, antimicrobial agents, antifungal agents, etc.

The term “additional anti-cancer agent” is used to describe ananti-cancer agent, which may be combined with compounds according to thepresent disclosure to treat cancer. These agents include, for example,everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib,GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457,MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFRinhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, aPARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TKinhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKTinhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase(mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin,tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab,ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402,lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel,atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil,vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

The term “anti-HIV agent” or “additional anti-HIV agent” includes, forexample, nucleoside reverse transcriptase inhibitors (NRTI), othernon-nucloeoside reverse transcriptase inhibitors (i.e., those which arenot representative of the present disclosure), protease inhibitors,fusion inhibitors, among others, exemplary compounds of which mayinclude, for example, 3TC (Lamivudine), AZT (Zidovudine), (−)-FTC, ddI(Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA),D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP(Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavirmesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV(Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors suchas T20, among others, fuseon and mixtures thereof, including anti-HIVcompounds presently in clinical trials or in development.

Other anti-HIV agents which may be used in coadministration withcompounds according to the present disclosure include, for example,other NNRTI's (i.e., other than the NNRTI's according to the presentdisclosure) may be selected from the group consisting of nevirapine(BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine,coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278),MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), InophyllumP, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324),Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-methylpyridyl)]thiourea {PETTPyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]-N′-[2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,3-[2-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one,Tivirapine (R86183), UC-38 and UC-84, among others.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastric juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present disclosure.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

General Synthetic Approach

The synthetic realization and optimization of the bifunctional moleculesas described herein may be approached in a step-wise or modular fashion.For example, identification of compounds that bind to the targetmolecules can involve high or medium throughput screening campaigns ifno suitable ligands are immediately available. It is not unusual forinitial ligands to require iterative design and optimization cycles toimprove suboptimal aspects as identified by data from suitable in vitroand pharmacological and/or ADMET assays. Part of the optimization/SARcampaign would be to probe positions of the ligand that are tolerant ofsubstitution and that might be suitable places on which to attach thelinker chemistry previously referred to herein. Where crystallographicor NMR structural data are available, these can be used to focus such asynthetic effort.

In a very analogous way one can identify and optimize ligands for an E3Ligase, i.e. ULMs/ILMs/VLMs/CLMs/ILMs.

With PTMs and ULMs (e.g. ILMs, VLMs, CLMs, and/or ILMs) in hand, oneskilled in the art can use known synthetic methods for their combinationwith or without a linker moiety. Linker moieties can be synthesized witha range of compositions, lengths and flexibility and functionalized suchthat the PTM and ULM groups can be attached sequentially to distal endsof the linker. Thus a library of bifunctional molecules can be realizedand profiled in in vitro and in vivo pharmacological and ADMET/PKstudies. As with the PTM and ULM groups, the final bifunctionalmolecules can be subject to iterative design and optimization cycles inorder to identify molecules with desirable properties.

In some instances, protecting group strategies and/or functional groupinterconversions (FGIs) may be required to facilitate the preparation ofthe desired materials. Such chemical processes are well known to thesynthetic organic chemist and many of these may be found in texts suchas “Greene's Protective Groups in Organic Synthesis” Peter G. M. Wutsand Theodora W. Greene (Wiley), and “Organic Synthesis: TheDisconnection Approach” Stuart Warren and Paul Wyatt (Wiley).

Protein Level Control

This description also provides methods for the control of protein levelswith a cell. This is based on the use of compounds as described herein,which are known to interact with a specific target protein such thatdegradation of a target protein in vivo will result in the control ofthe amount of protein in a biological system, preferably to a particulartherapeutic benefit.

The following examples are used to assist in describing the presentdisclosure, but should not be seen as limiting the present disclosure inany way.

General Synthetic Approach

The synthetic realization and optimization of the bifunctional moleculesas described herein may be approached in a step-wise or modular fashion.For example, identification of compounds that bind to the targetmolecules can involve high or medium throughput screening campaigns ifno suitable ligands are immediately available. It is not unusual forinitial ligands to require iterative design and optimization cycles toimprove suboptimal aspects as identified by data from suitable in vitroand pharmacological and/or ADMET assays. Part of the optimization/SARcampaign would be to probe positions of the ligand that are tolerant ofsubstitution and that might be suitable places on which to attach thelinker chemistry previously referred to herein. Where crystallographicor NMR structural data are available, these can be used to focus such asynthetic effort.

In a very analogous way one can identify and optimize ligands for an E3Ligase, i.e. ULMs/VLMs/CLMs/ILMs/MLMs.

With PTMs and ULMs (e.g. VLMs, CLMs, ILMs, and/or MLMs) in hand, oneskilled in the art can use known synthetic methods for their combinationwith or without a linker moiety. Linker moieties can be synthesized witha range of compositions, lengths and flexibility and functionalized suchthat the PTM and ULM groups can be attached sequentially to distal endsof the linker. Thus, a library of bifunctional molecules can be realizedand profiled in vitro and in vivo pharmacological and ADMET/PK studies.As with the PTM and ULM groups, the final bifunctional molecules can besubject to iterative design and optimization cycles in order to identifymolecules with desirable properties.

Compounds of the present disclosure [e.g., the general Formula PTM-I orPTM-II] may be prepared by methods known in the art of organic synthesisas set forth in the specific Examples described herein. In all of themethods, it is well understood that protecting groups for sensitive orreactive groups may be employed where necessary in accordance withgeneral principles of chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (T. W. Green and P.G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley & Sons). These groups are removed at a convenientstage of the compound synthesis using methods that are readily apparentto those skilled in the art. The selection of processes as well as thereaction conditions and order of their execution shall be consistentwith the preparation of compounds of the present disclosure, includingcompounds of Formula (I). Schemes described below illustrate the generalmethods of preparing compounds with the structure featured as Formula(I) and Formula (II).

Abbreviations

ACN: acetonitrile

ADDP: 1,1′-(azodicarbonyl)dipiperidine

BOP: (Benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate

DCE: 1,2-dichloroethane

DCM: dichloromethane

DEAD: diethyl azodicarboxylate

DIEA or DIPEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DME: Dimethoxyethane

DMF: N,N-dimethylformamide

DMP: Dess-Martin periodinane

ES⁺: electron spary with positive charge

h: hour.

HATU: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate.

HPLC: high-performance liquid chromatography

LC-MS: liquid chromatography-mass spectrometry

Min: minutes.

NBS: N-bromosuccinimide

NMP: N-methylpyrrolidone

NMR: Nuclear magnetic resonance

RT or t_(R): retention time

SFC: supercritical fluid chromatography

TBAC: tetrabutylammonium chloride

TCCA: Trichloroisocyanuric acid

TFA: trifluoroacetic acid.

THF: tetrahydrofuran.

TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide

XPhos: 2-dicyclohexylphosphino-2′4′6′-triisopropylbiphenyl

General Conditions and Analytical Methods

All solvents used were commercially acquired and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of nitrogen. Flash columnchromatography was generally carried out using Silica gel 60(0.035-0.070 mm particle size).

The synthesis of the claimed compounds can be carried out according tothe following schemes. Synthetic routes in these schemes are describedas the representative methods. Other methods can also be used for thoseskilled in the art of synthesis.

General Synthetic Scheme 1 to Prepare Intermediates

General Synthetic Scheme 2 to Prepare Intermediates

General Synthetic Scheme 3 to Prepare Intermediates

General Synthetic Scheme 4 to Prepare Intermediates

General Synthetic Scheme 5 to Prepare Intermediates

General Synthetic Scheme 6 to Prepare Intermediates

General Synthetic Scheme 7 to Prepare Intermediates

General Synthetic Scheme 8 to Prepare Intermediates

General Synthetic Scheme 9 to Prepare Intermediates

General Synthetic Scheme 10 to Prepare Intermediates

General Synthetic Scheme 11 to Prepare Intermediates

General Synthetic Scheme 12 to Prepare Intermediates

General Synthetic Scheme 13 to Prepare Intermediates.

General Synthetic Scheme 14.

General Synthetic Scheme 15.

General Synthetic Scheme 16.

General Synthetic Scheme 17.

General Synthetic Scheme 18.

General Synthetic Scheme 19.

General Synthetic Scheme 20.

General Synthetic Scheme 21.

General Synthetic Scheme 22.

General Synthetic Scheme 23.

General Synthetic Scheme 24.

General Synthetic Scheme 25.

General Synthetic Scheme 26.

General Synthetic Scheme 27.

General Synthetic Scheme 28.

General Synthetic Scheme 29.

General Synthetic Scheme 30.

General Synthetic Scheme 31.

General Synthetic Scheme 32.

General Synthetic Scheme 33.

General Scheme 1A to Prepare Intermediates

General Scheme 2A to Prepare Intermediates

General Scheme 3A to Prepare Intermediates

General Scheme 4A to Prepare Intermediates

General Scheme 5A to Prepare Intermediates

General Scheme 6A to Prepare Intermediates

General scheme 7A to Prepare Intermediates

General Scheme 8A to Prepare Intermediates

General Scheme 9A to Prepare Intermediates

General Scheme 10A to Prepare Intermediates

General Scheme 11A to Prepare Intermediates

General Scheme 12A to Prepare Intermediates

General Scheme 13A to Prepare Intermediates

General Scheme 14A to Prepare Intermediates

General Scheme 15A to Prepare Intermediates

General Scheme 16A to Prepare Intermediates

General Scheme 17A to Prepare Intermediates

General Scheme 18A to Prepare Compound in Compound 111.

General Scheme 19A to Prepare Compound in Compound 140.

General Scheme 20A to Prepare Compound in Example 161, 162, 163, 164,165 and 166.

General Scheme 1B to Prepare Compound 170.

General Scheme 2B to Prepare Compound 174.

General Scheme 3B to Prepare Compound 175.

General Scheme 4B to Prepare Compound 177.

General Scheme 5B to Prepare Compound 178.

General Scheme 6B to Prepare Compound 180.

General Scheme 7B to Prepare Compound 182.

General Scheme 8B to Prepare Compound 183.

General Scheme 9B to Prepare Compound 184.

General Scheme 10B to Prepare Compound 185.

General Scheme 11B to Prepare Intermediate for Compound 186.

General Scheme 12B to Prepare Compound 187.

General Scheme 13B to Prepare Intermediate for Compound 188.

General Scheme 14B to Prepare Compound 189.

General Scheme 15B to Prepare Intermediate for Compound 190.

General Scheme 16B to Prepare Intermediate for Compound 192.

General scheme 17B to prepare intermediate for compound 193.

General Scheme 18B to Prepare Intermediate for Compound 197.

General Scheme 19B to Prepare Intermediate for Compound 198.

General Scheme 20B to Prepare Intermediate for Compound 206.

General Scheme 21B to Prepare Intermediate for Compound 204.

General scheme 22B to prepare compound 207.

General scheme 23B to prepare compound 209.

General Scheme 24B to Prepare Compound 211.

General scheme 25B to prepare compound 212.

General Scheme 26B to Prepare Compound 213.

General Scheme 27B to Prepare Compounds 214 and 216.

General Scheme 28B to Prepare Intermediate for Compound 218.

General Scheme 29B to Prepare Intermediate for Compound 222.

General Scheme 30B to Prepare Compound 223.

General Scheme 31B to Prepare Compound 224.

General Scheme 32B to Prepare Intermediate for Compound 225.

General Scheme 33B to Prepare Compound 226.

General Scheme 34B to Prepare Intermediate for Compound 230.

General Scheme 35B to Prepare Compound 231.

General Scheme 36B to Prepare Intermediate for Compound 232.

General Scheme 37B to Prepare Intermediate for Compound 238.

General Scheme 38B to Prepare Compound 240.

General Scheme 39B to Prepare Intermediate for Compound 241.

General Scheme 40B to Prepare Compound 242.

General Scheme 41B to Prepare Compounds 243, 244 and 245.

Experiment Procedures of Synthesizing ER PROTACs Preparation of2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophene-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}acetamide(Compound 11)

Step 1: Preparation of 1-(4-benzyloxyphenoxy)propan-2-one

To a solution of 4-benzyloxyphenol (3 g, 14.98 mmol, 1.00 eq) in acetone(30 mL) was added potassium carbonate (2.48 g, 17.98 mmol, 1.20 eq) and1-bromopropan-2-one (2.46 g, 17.98 mmol, 1.20 eq) under nitrogenatmosphere. The reaction mixture was stirred at 60° C. for 5 h. LC/MSshowed most of the starting material was consumed. Water (150 mL) wasadded to the mixture, the resulting mixture was extracted with petroleumether (50 mL×3). The combined organic phase was washed with brine (80mL), dried over sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether:Ethylacetate=30/1 to 3/1) to give 1-(4-benzyloxyphenoxy)propan-2-one (3.3 g,crude) as a white solid.

LC/MS: MS (ESI) m/z: 257.0 [M+1]⁺; ¹H NMR: (400 MHz, CDCl₃)

δ: 7.44-7.33 (m, 5H), 6.94-6.90 (m, 2H), 6.84-6.82 (m, 2H), 5.03 (s,2H), 4.50 (s, 2H), 2.28 (s, 3H).

Step 2: Preparation of tert-butyl4-[2-(4-benzyloxyphenoxy)-1-methyl-ethyl]piperazine-1-carboxylate

To a solution of 1-(4-benzyloxyphenoxy) propan-2-one (1.8 g, 7.02 mmol,1.00 eq) in 1,2-dichloroethane (30 mL) was added tert-butylpiperazine-1-carboxylate (1.05 g, 5.62 mmol, 0.80 eq) and acetic acid(421 mg, 7.02 mmol, 0.41 mL, 1.00 eq). The mixture was stirred at 20° C.for 1 h. Then sodium triacetoxyborohydride (2.23 g, 10.53 mmol, 1.50 eq)was added to the mixture, the reaction was stirred at 20° C. for 5 h.LC/MS showed most of the starting material was consumed. Water (150 mL)and dichloromethane (80 mL) was added to the mixture, and layers wereseparated. The organic layer was washed with brine (50 mL), dried oversodium sulfate, filtered and concentrated in vacuum. The residue waspurification by silica gel chromatography (Petroleum ether/Ethylacetate=30/1 to 1/1) to give tert-butyl4-[2-(4-benzyloxyphenoxy)-1-methyl-ethyl]piperazine-1-carboxylate (1.4g, 3.28 mmol, 47% yield) as a light yellow oil.

LCMS: MS (ESI) m/z: 427.1 [M+1]⁺; ¹H NMR: (400 MHz, CDCl₃) δ: 7.44-7.30(m, 5H), 6.94-6.90 (m, 2H), 6.85-6.82 (m, 2H), 5.02 (s, 2H), 4.02-3.98(m, 1H), 3.85-3.81 (m, 1H), 3.43 (t, J=4.8 Hz, 4H), 3.05-2.97 (m, 1H),2.65-2.55 (m, 4H), 1.46 (s, 9H), 1.16 (d, J=6.8 Hz, 3H).

Step 3: Preparation of tert-butyl4-[2-(4-hydroxyphenoxy)-1-methyl-ethyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[2-(4-benzyloxyphenoxy)-1-methyl-ethyl]piperazine-1-carboxylate (1.4g, 3.28 mmol, 1.00 eq) in methanol (40 mL) was added Pd/C (200 mg, 10%)under nitrogen atmosphere. The suspension was degassed under vacuum andpurged with hydrogen several times. The reaction mixture was stirred at20° C. for 16 h under hydrogen (50 psi). TLC (Petroleum ether/Ethylacetate=1/1) showed most of the starting material was consumed. Themixture was filtered and the filtrate was concentrated in vacuum to givetert-butyl4-[2-(4-hydroxyphenoxy)-1-methyl-ethyl]piperazine-1-carboxylate (1 g,2.97 mmol, 91% yield) as a yellow oil.

¹H NMR: (400 MHz, CDCl₃) δ: 8.78-8.73 (m, 4H), 4.00-3.96 (m, 1H),3.84-3.80 (m, 1H), 3.44 (t, J=4.8 Hz, 4H), 3.03-2.99 (m, 1H), 2.64-2.58(m, 4H), 1.46 (s, 9H), 1.17 (d, J=6.8 Hz, 3H).

Step 4: Preparation of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylateStep 4-1: Preparation of3-Bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene

To a solution of KOH (25 g 10 eq) in ethanol (1 L) at 15-25° C. wasadded 3-methoxybenzenethiol (54 g, 1.1 eq) and the mixture was stirredat 15-25° C. for 30 min. Then the mixture was cooled to 0° C. and ethylacetate (700 mL) and 2-bromo-1-(4-bromophenyl)ethanone (80 g, 1.0 eq)were added subsequently at 0° C. The mixture was stirred at 0° C. for 30min. The reaction mixture was warmed to rt and stirred for 4 h. Then thesolvent was removed under reduced pressure. The residue was extractedwith ethyl acetate (500 mL×2), washed with brine (300 mL), and driedover anhydrous Na₂SO₄. The solvent was removed under reduced pressure.The residue was recrystallized from CH₃OH (500 mL) to afford1-(4-bromophenyl)-2-(3-methoxyphenylthio)ethanone as a yellow solid (100g, 87%). ¹HNMR (400 MHz, CDCl₃) δ: 7.80 (d, J=8.8 Hz, 2H), 7.61 (d,J=8.8 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.91 (t,J=2.0 Hz, 1H), 6.77 (dd, J=8.0, 1.6 Hz, 1H), 4.23 (s, 2H), 3.78 (s, 3H).

To a stirring solution of PPA (1 L) at 80° C. (keep stirring as fast aspossible) was added 1-(4-bromophenyl)-2-(3-methoxyphenylthio)ethanone(100 g, 1.0 eq) in portions within 40 min (control the temperature below95° C.). Then the reaction was heated to 90° C. and stirred for 2 h. Thesolution was stirred at 130˜135° C., for another 16 h. The mixture wascooled to 50-70° C. The reaction mixture was poured into ice water (1.5L) and stirred for 1 h. The crude product was collected by filtrationand the solid was washed with water, and recrystallized with EA toafford 2-(4-bromophenyl)-6-methoxybenzo[b]thiophene as a pale solid 51 g(yield: 52.6%). ¹HNMR (400 MHz, DMSO) δ: 7.86 (s, 1H), 7.57-7.82 (m,6H), 7.01-7.03 (m, 1H), 3.84 (s, 3H).

To a suspended mixture of 2-(4-bromophenyl)-6-methoxybenzo[b]thiophene(46 g, 1.0 eq) in dried DCM (1 L) was added N-bromosuccinimide (26 g,1.02 eq) at 20° C. The reaction mixture was stirred at room temperaturefor 5 h and then quenched by addition of water (500 mL). The mixture wasextracted with DCM and the combined organic layers were dried overanhydrous sodium sulfate and the solution was concentrated under vacuum.The residue was recrystallized with EA to afford3-bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene as a light purplesolid (50.0 g, 88%). ¹HNMR (400 MHz, DMSO) δ: 7.67-7.77 (m, 6H), 77.18(d, J=7.2 Hz, 1H), 3.87 (s, 3H).

Step 4-2: Preparation of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate

To a solution of 3-bromo-2-(4-bromophenyl)-6-methoxy-benzothiophene(1.80 g, 4.52 mmol, 1.00 eq) in dichloromethane (18 mL) was drop-wiseadded trifluoroacetic acid (15 mL). Hydrogen peroxide (769 mg, 6.78mmol, 0.65 mL, 30% aq. solution, 1.50 eq) was added. The mixture wasstirred at 18° C. for 2 h. TLC (petroleum ether:ethyl acetate=3:1,R_(f)=0.24) showed the reaction was completed and a new spot formed. Thereaction mixture was quenched by adding saturated sodium sulfite (5 mL)and the mixture was stirred at 18° C. for 10 min, then the mixture wasadjusted to pH=(7˜8) with saturated sodium bicarbonate (150 mL). Thesolution was extracted with dichloromethane (50 mL×3). The combinedorganic phase was washed with saturated brine (50 mL×2), dried withanhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by silica gel column chromatography (petroleumether:ethyl acetate=10:1 to 1:1) to afford3-bromo-2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium (1.10 g,2.66 mmol, 59% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ:7.73-7.63 (m, 4H), 7.59 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.16(dd, J=2.4, 8.4 Hz, 1H), 3.94 (s, 3H).

To a solution of tert-butyl4-[2-(4-hydroxyphenoxy)-1-methyl-ethyl]piperazine-1-carboxylate (1.0 g,2.97 mmol, 1.00 eq) in N,N-dimethylformamide (10 mL) was added sodiumhydride (143 mg, 3.57 mmol, 60% in mineral oil, 1.20 eq) at 0° C. Themixture was stirred at 20° C. for 0.5 h. Then3-bromo-2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium (1.23 g,2.97 mmol, 1.00 eq) was added, the reaction mixture was stirred at 20°C. for 1 h. TLC (dichloromethane/methanol=20/1) showed most of thestarting material was consumed. Saturated ammonium chloride (100 mL) wasadded to the mixture, the resulting mixture was extracted with ethylacetate (50 mL×3). The combined organic phase was washed with brine (100mL), dried over sodium sulfate, filtered and concentrated in vacuum togive tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate(2 g, crude) as a yellow oil. LC/MS: MS (ESI) m/z: 668.8, 670.8 [M,M+2]⁺.

Step 5: Preparation of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate(2 g, 2.54 mmol, 1.00 eq) in acetonitrile (20 mL) was added sodiumiodide (1.14 g, 7.62 mmol, 3.00 eq) and trimethyl chlorosilane (552 mg,5.08 mmol, 2.00 eq). The reaction mixture was stirred at 20° C. for 3 h.LC/MS showed most of the starting material was consumed. The reactionwas quenched with saturated sodium thiosulfate (50 mL), the resultingmixture was extracted with ethyl acetate (30 mL×3). The combined organicphase was washed with brine (40 mL), dried over sodium sulfate, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=30/1 to 0/1) to givetert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate(1.5 g, 2.29 mmol, 90% yield) as a yellow solid. LC/MS: MS (ESI) m/z:653.1, 655.1 [M, M+2]⁺. ¹H NMR: (400 MHz, CD₃Cl₃) δ: 7.64-7.61 (m, 2H),7.30-7.26 (m, 3H), 6.90-6.88 (m, 3H), 6.80-6.78 (m, 2H), 3.99-3.95 (m,1H), 3.88 (d, J=1.6 Hz, 3H), 3.82-3.79 (m, 1H), 3.42 (t, J=4.0 Hz, 4H),3.02-2.97 (m, 1H), 2.63-2.58 (m, 4H), 1.46 (d, J=8.0 Hz, 9H), 1.15 (d,J=5.6 Hz, 3H).

Step 6: Preparation of1-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine

To a solution of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate(800 mg, 1.22 mmol, 1.00 eq) in dichloromethane (5 mL) was addedhydrochloric acid/dioxane (4 M, 3 mL, 9.51 eq). The mixture was stirredat 20° C. for 1 hour. The reaction mixture was concentrated underreduced pressure to remove dichloromethane and dioxane to give1-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine(700 mg, 1.19 mmol, 97% yield, hydrochloride) as a white solid. LCMS: MS(ESI) m/z: 555.0 [M+1]⁺.

Step 7: Preparation of methyl2-(4-(1-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)propan-2-yl)piperazin-1-yl)acetate

To a solution of1-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine(720 mg, 1.22 mmol, 1.00 eq, hydrochloride) in N,N-dimethylformamide (10mL) was added potassium carbonate (506 mg, 3.66 mmol, 3.00 eq) andmethyl 2-bromoacetate (224 mg, 1.46 mmol, 0.14 mL, 1.20 eq). The mixturewas stirred at 20° C. for 16 hours. LC/MS showed the reaction wascompleted and the desired MS was detected. The reaction mixture wasdiluted with water (40 mL) and extracted with ethyl acetate (30 mL×3).The combined organic phase was washed with saturated brine (40 mL×2),dried with anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was purified by silica gel column chromatography(petroleum ether:ethyl acetate=6:1 to 1:1) to give methyl2-{4-[1-(4-{[2-(4-bromophenyl)-6-methoxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate(500 mg, 0.8 mmol, 66% yield) as a yellow oil. LCMS: MS (ESI) m/z: 627.1[M+1]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ: 7.65-7.58 (m, 2H), 7.49-7.45 (m, 2H),7.30-7.23 (m, 2H), 6.91-6.83 (m, 3H), 6.81-6.74 (m, 2H), 4.03-3.94 (m,1H), 3.87 (s, 3H), 3.85-3.76 (m, 1H), 3.74-3.71 (m, 3H), 3.22 (s, 2H),3.05-2.98 (m, 1H), 2.82-2.59 (m, 8H), 2.05 (s, 1H), 1.21-1.16 (m, 3H).

Step 8: Preparation of2-(4-(1-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)propan-2-yl)piperazin-1-yl)aceticacid

To a solution of methyl2-{4-[1-(4-{[2-(4-bromophenyl)-6-methoxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate(500 mg, 0.8 mmol, 1.00 eq) in dichloromethane (10 mL) was added borontribromide (600 mg, 2.40 mmol, 0.23 mL, 3.00 eq) at −70° C. The mixturewas stirred at 20° C. for 16 hours. LC/MS showed the reaction wascompleted and the desired product was formed. The reaction mixture wasquenched with methanol (10 mL) at 0° C. and concentrated under reducedpressure to remove methanol and dichloromethane to give2-(4-(1-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)propan-2-yl)piperazin-1-yl)aceticacid (380 mg, crude) as a yellow oil, which was directly used for nextstep without further purification. LCMS: MS (ESI) m/z: 599.0 [M+1]⁺.

Step 9: Preparation of methyl2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate

To a solution of2-{4-[1-(4-{[2-(4-bromophenyl)-6-methoxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}aceticacid (380 mg, 0.64 mmol, 1.00 eq) in methanol (10 mL) was added sulfuricacid (184 mg, 1.88 mmol, 0.1 mL, 2.95 eq). The mixture was stirred at70° C. for 12 hours. LC/MS showed the reaction was completed and thedesired product was formed. The reaction mixture was adjusted topH=(8-9) with sodium bicarbonate (2M, 4 mL), and diluted with water (30mL) and extracted with ethyl acetate (20 mL×2). The combined organicphase was washed with saturated brine (20 mL×2), dried with anhydroussodium sulfate, filtered and concentrated in vacuum. The residue waspurified by prep-TLC (Dichloromethane:Methanol=10:1) to give desiredcompound (200 mg, yield 51%, purity 92%) as a white solid, which wasfurther separated by chiral SFC (AD column, 250 mm×30 mm, 10 m, 0.1%NH₃.H₂O in IPA) to give methyl 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-

hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate(90 mg, 0.15 mmol, 23% yield) as a yellow oil and methyl2-{4-[(2S)-1-(4-{[2-(4-bromophenyl)-6-

hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate(90 mg, 0.15 mmol, 23% yield) as a yellow oil. LCMS: MS (ESI) m/z: 613.0[M+1]⁺.

Step 10: Preparation of2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}aceticacid

To a solution of methyl2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate(90 mg, 0.15 mmol, 1.00 eq) in tetrahydrofuran (1 mL) and methanol (2mL) was added lithium hydroxide monohydrate (2 M, 0.5 mL, 6.79 eq). Themixture was stirred at 20° C. for 2 hours. The reaction mixture wasquenched with hydrochloric acid (2M, 0.6 mL). The mixture wasconcentrated under reduced pressure to remove methanol, tetrahydrofuranand water to give2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}aceticacid (95 mg, crude) as a white solid, which was directly used for nextstep without further purification. LCMS: MS (ESI) m/z: 598.9 [M+1]⁺.

Step 11: Preparation of2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}acetamide

To a solution of2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}aceticacid (85 mg, 0.14 mmol, 1.00 eq) and3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (64 mg,0.14 mmol, 1.00 eq) in N,N-dimethylformamide (3 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (65 mg, 0.17 mmol, 1.20 eq) anddiisopropylethylamine (92 mg, 0.7 mmol, 0.1 mL, 5.00 eq). The mixturewas stirred at 20° C. for 12 h. LC/MS showed the reaction was completedand the desired product was formed. The reaction mixture was purified byprep-HPLC (column: Boston Green ODS 150 mm×30 mm, 5 m; mobile phase:water with 0.225% TFA as solvent A and acetonitrile as solvent B;gradient: 27% B-57% B in 10 min). Then the collected fraction wasconcentrated to remove most of acetonitrile and hydrochloric acid (1 M,2 mL) was added. The solution was lyophilized to give2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}acetamide(54 mg, 0.06 mmol, 43% yield, 98% purity, hydrochloride) as a yellowsolid. LCMS: MS (ESI) m/z: 852.2 and 854.2 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ: 10.99 (s, 1H), 9.98 (s, 1H), 9.14-8.78 (m, 1H), 7.69 (d,J=8.0 Hz, 1H), 7.61 (s, 4H), 7.51 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33(d, J=2.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.99-6.89 (m, 4H), 6.84 (dd,J=2.0, 8.8 Hz, 1H), 5.11 (dd, J=5.2, 13.2 Hz, 1H), 4.56-4.11 (m, 7H),4.02-3.53 (m, 10H), 2.96-2.87 (m, 1H), 2.65-2.55 (m, 1H), 2.43-2.35 (m,1H), 2.05-1.95 (m, 1H), 1.53 (br d, J=6.4 Hz, 1H), 1.38 (s, 2H).

Preparation of5-{4-[5-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)pentyl]piperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(Compound 61)

Step 1: Preparation of 4-(5-hydroxypentyloxy)phenol

To a solution of 4-hydroxyphenol (3.0 g, 27.3 mmol) in water (30 mL) wasadded sodium hydroxide (1.45 g, 36.4 mmol) and 5-bromopentan-1-ol (4.5g, 27.3 mmol). The mixture was heated to 100° C. for 6 h under N₂ gas.After cooling to rt, hydrochloric acid (1.0 M) was added to adjust pH to1.0. The mixture was extracted with ethyl acetate (50 mL×3). The organiclayer was washed with brine (50 mL). The combined organic phases weredried over anhydrous sodium sulfate, filtered, and concentrated in vacuoand purified by silica gel (petroether/ethyl acetate=3:1) to provide4-(5-hydroxypentyloxy)phenol (1.5 g, 48.7%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.51-1.54 (2H, m), 1.61-1.66 (2H, m),1.76-1.83 (2H, m), 3.68 (2H, t, J=6.6 Hz), 3.91 (2H, t, J=6.4 Hz), 4.61(1H, s), 6.73-6.79 (4H, m).

Step 2: Preparation of6-(benzyloxy)-2-(4-bromophenyl)-3-{4-[(5-hydroxypentyl)oxy]phenoxy}-1H-1-benzothiophen-1-ium-1-olate

To a solution of 4-(5-hydroxypentyloxy)phenol (100 mg, 0.5 mmol) in DMF(5 mL) was added6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-1H-1-benzothiophen-1-ium-1-olate(400 mg, 0.82 mmol) and potassium carbonate (170 mg, 1.23 mmol). Themixture was heated to 60° C. for 3 h under N₂ gas. After cooling to rt,the reaction mixture was diluted with water (10 mL), and the mixture wasextracted with ethyl acetate (10 mL×3). The organic layer was washedwith brine (10 mL×3). The combined organic phases were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to give6-(benzyloxy)-2-(4-bromophenyl)-3-{4-[(5-hydroxypentyl)oxy]phenoxy}-1H-1-benzothiophen-1-ium-1-olate(200 mg, 64.9%) as yellow oil, which was used to next step withoutfurther purification.

Step 3: Preparation of5-(4-{[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy}phenoxy)pentan-1-ol

To a solution of6-(benzyloxy)-2-(4-bromophenyl)-3-{4-[(5-hydroxypentyl)oxy]phenoxy}-1H-1-benzothiophen-1-ium-1-olate(200 mg, 0.33 mmol) in acetonitrile (10 mL) was addedchlorotrimethylsilane (30 mg, 0.3 mmol) and potassium iodide (50 mg, 0.3mmol). The reaction mixture was stirred at room temperature for 2 h. Themixture was treated with water (10.0 mL) and then extracted withdichloromethane (10.0 mL×2). The combined organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo and purified by preparative TLC to give5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentan-1-ol(140 mg, 71.8%) as a yellow solid.

Step 4: Preparation of5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentanal

To a solution of5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentan-1-ol(200 mg, 0.34 mmol) in dichloromethane (20 mL) was added Dess-Martinperiodinane (0.44 g, 1.02 mmol). The mixture was stirred at roomtemperature for 1 h. The mixture was diluted with water (20.0 mL) andextracted with dichloromethane (20.0 mL×2). The combined organic layerwas washed with brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo and purified by preparative TLC togive5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentanal(120 mg, 60.2%) as a yellow solid.

Step 5: Preparation of5-(4-(2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)pentanal

To a solution of5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentanal(150 mg, 0.2 mmol) in dichloromethane (20 mL) was added boron tribromide(0.30 mL, 1.0 M) at −78° C. and stirred for 30 min at this temperature.The reaction mixture was diluted with water (10 mL) and sodiumbicarbonate (5 mL), and then extracted with EtOAc (10 mL×3). The organiclayer was washed with brine (20 mL). The combined organic phases weredried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The residue was purified by pre-TLC (petroleum ether/ethylacetate=3:1) to provide5-(4-(2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)pentanal(62 mg, 61.1%) as a white solid.

Step 6: Preparation of5-{4-[5-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)pentyl]piperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione

To a solution of5-(4-(2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)pentanal(62 mg, 0.125 mmol) in dry DCM/MeOH/HOAc (2 mL/2 mL/0.1 mL) was added2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (43mg, 0.125 mmol). The mixture was left to stir for 30 min under N₂ gas.Then sodium triacetoxyborohydride (79.5 mg, 0.375 mmol) was added andthe reaction mixture was left to stir overnight. The solvent was removedand the residue was partitioned between dichloromethane and water. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give a crude product.The residue was purified by pre-HPLC to afford5-{4-[5-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)pentyl]piperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(35 mg, 33.5%) as a yellow solid.

LC-MS: MS (ESI) m/z 823.2, 825.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ1.40-1.54 (4H, m), 1.66-1.73 (2H, m), 1.99-2.02 (1H, m), 2.31 (2H, t,J=7.4 Hz), 2.47-2.51 (5H, m), 2.53-2.60 (1H, m), 2.83-2.93 (1H, m),3.36-3.41 (4H, m), 3.88 (2H, t, J=6.2 Hz), 5.07 (1H, dd, J=5.2, 12.8Hz), 6.82 (1H, dd, J=2.0, 8.4 Hz), 6.86 (4H, s), 7.15 (1H, d, J=8.8 Hz),7.24 (1H, dd, J=2.0, 8.4 Hz), 7.32 (2H, dd, J=1.6, 9.6 Hz), 7.62 (4H,s), 7.67 (1H, d, J=8.8 Hz), 9.92 (1H, s), 11.08 (1H, s).

Preparation of Intermediates Intermediate 1:(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamidehydrochloride

Reagents and conditions: (a) (Boc)₂O, NaHCO₃, EtOAc/H₂O; (b) (1)Pd(OAc)₂, KOAc, 90° C.; (2) 4N HCl in MeOH; (c) (1) HATU, DIPEA, DMF;(2) LiOH, THF, H₂O; (d) (1) intermediate compound 3, HATU, DIPEA, THF;(2) 4N HCl in MeOH

Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethyl carbamate(2)

To a mixture of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) andNaHCO₃ (1.24 g, 14.8 mmol) in H₂O (10 mL) and ethyl acetate (10 mL) wasadded (Boc)₂O (5.20 g, 23.8 mmol) at 5° C. The reaction was continued toreact for 2 hours. TLC showed the reaction was complete. The reactionmixture was filtered. The solid was collected and suspended in a mixtureof hexane (10 mL) and H₂O (10 mL) for 0.5 h. The mixture was filteredand the solid was collected and dried in oven at 50° C. to afford thetitle compound as white solid (5.9 g, 98.7%). ¹HNMR (400 MHz, DMSO-d₆):δ 1.28 (d, J=7.2 Hz, 3H), 1.36 (s, 9H), 4.55-4.60 (m, 1H), 7.25 (d,J=8.4 Hz, 2H), 7.39 (br, 1H), 7.49 (d, J=8.4 Hz, 2H).

Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanaminehydrochloride (3)

A mixture of intermediate compound 2 (4.0 g, 13.3 mmol),4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg,0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) inN,N-dimethylacetamide (10 mL) was stirred at 90° C. under N₂ for 18 h.After cooling to ambient temperature, the reaction mixture was filtered.To the filtrate was added H₂O (50 mL) and the resulting mixture wasstirred at ambient temperature for 4 h. The reaction mixture wasfiltered. The solid was collected by filtration and dried in oven at 50°C. to afford (S)-tert-butyl1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as graysolid. ¹HNMR (400 MHz, DMSO-d₆): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H),2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz,2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS[M+1]⁺: 319.5

This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloridein methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol)and the mixture was stirred at ambient temperature for 3 h. the mixturewas filtered and the solid was collected and dried in oven at 60° C. toafford (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride(1.3 g, 85%) as a light green solid. ¹HNMR (400 MHz, DMSO-d6): δ 1.56(d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J=8.4 Hz,2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1]⁺: 219.2

Step 3: Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylicacid (6)

HATU (2.15 g, 5.7 mmol) was added to a solution of(S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoic acid (1.25 g, 5.4mol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride(0.98 g, 5.4 mmol) and DIPEA (2.43 g, 18.9 mmol) in DMF (10 mL) at 0° C.under nitrogen. The mixture was stirred at ambient temperature for 18hours. TLC showed the reaction complete. The reaction mixture wasquenched with water (30 mL) and extracted with ethyl acetate (15 mL×4).The combined organic layer was washed with the 5% citric acid (10 mL×2),saturated NaHCO₃ solution (10 mL×2), brine (10 mL×2) and dried overNa₂SO₄. The organic solution was filtered and concentrated to afford(2S, 4R)-methyl1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylateas pale yellow oil (1.93 g, 100% yield). This crude product (1.93 g) andlithium hydroxide hydrate (2.2 g, 54 mmol) were taken into THF (20 mL)and H₂O (10 mL). The resulting mixture was stirred at ambienttemperature for 18 h. THF was removed by concentration. The residue wasdiluted with ice-water (10 mL) and slowly adjusted to pH 2-3 with 3NHCl. The resulting suspension was filtered, washed with H₂O (6 mL×2).The solid was collected by filtration and dried in oven at 50° C. toafford the title compound as a white solid (1.4 g, 75% for two steps).¹HNMR (400 MHz, DMSO-d₆): δ 6.50 (d, J=9.6 Hz, 1H), 5.19 (br s, 1H),4.32 (br s, 1H), 4.25 (t, J=8.4 Hz, 1H), 4.16 (d, J=9.2 Hz, 1H),3.57-3.66 (m, 2H), 2.08-2.13 (m, 1H), 1.85-1.91 (m, 1H), 1.38 (s, 9H),0.94 (s, 9H).

Step 4: Preparation of(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamidehydrochloride (7)

HATU (1.6 g, 4.2 mmol) was added to a stirred solution of intermediatecompound 6 (1.21 g, 3.5 mmol), intermediate compound 3 (0.9 g, 3.5mmol), and DIPEA (1.36 g, 10.5 mmol) in anhydrous THF (15 mL) at 0° C.The resulting mixture was allowed to warm up to ambient temperature andcontinued to stir for 2 hours. TLC showed reaction complete. THF wasremoved by concentration. To the residue was added water (15 mL) and theresulting mixture was stirred for 4 hours. The resulting mixture wasfiltered. The solid was collected and dried in oven at 50° C. to give awhite solid. This solid was taken into methanol (10 mL) and activatedcarbon (150 mg) was added. The resulting mixture was heated at 80° C.and stirred for 1 hour. The mixture was filtered while it was hot. Water(5 mL) was added to the filtrate at 80° C. The resulting mixture wascooled to ambient temperature and continued to stir for 18 hours. Thesuspension was filtered. The solid was collected and dried in oven at50° C. to affordtert-butyl-{(S)-1-[(2S,4R)-4-hydroxy]-2-[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutan-2-yl-carbamate(1.41 g, 74.2%) as white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.05 (s, 9H),1.42 (s, 9H), 1.47 (d, J=7.2 Hz, 3H), 2.04-2.10 (m, 1H), 2.53 (s, 3H),2.58-2.64 (m, 1H), 3.23 (s, 1H), 3.58 (dd, J=11.2 Hz, 3.2 Hz, 1H), 4.11(d, J=11.6 Hz, 1H), 4.22 (d, J=9.2 Hz, 1H), 4.51 (br, 1H), 4.79 (t,J=8.0 Hz, 1H), 5.04-5.11 (m, 1H), 5.22 (d, J=8.8 Hz, 1H), 7.36-7.42 (m,4H), 7.61 (d, J=7.6 Hz 1H), 8.68 (s, 1H). This solid (1.04 g, 1.9 mmol)was dissolved in 4N hydrogen chloride in methanol (3.0 mL) and themixture was stirred at ambient temperature for 3 hours. TLC showedreaction complete. The reaction mixture was concentrated to remove allvolatiles under reduced pressure to give a light yellow solid. The solidwas added to TBME (5 mL) and the resulting mixture was stirred atambient temperature for 4 h. The reaction mixture was filtered and thesolid was collected and dried in oven at 50° C. to afford intermediatecompound 7 (0.92 g, 100%). ¹H NMR (400 MHz, DMSO-d6): δ 1.03 (s, 9H),1.38 (d, J=7.2 Hz, 3H), 1.72-1.79 (m, 1H), 2.09-2.14 (m, 1H), 2.49 (s,3H), 3.48-3.52 (m, 1H), 3.75-3.79 (m, 1H), 3.88-3.90 (m, 1H), 4.31 (br,1H), 4.56 (t, J=8.4 Hz, 1H), 4.89-4.95 (m, 1H), 7.41 (d, J=8.4 Hz, 2H),7.47 (d, J=8.4 Hz, 2H), 8.20 (br, 3H), 8.67 (d, J=7.6 Hz, 1H), 9.22 (s,1H); ¹³C NMR (400 MHz, DMSO-d6): δ 170.7, 167.1, 153.0, 146.5, 145.7,132.5, 129.4, 129.3, 126.9, 69.4, 59.3, 58.5, 56.9, 48.3, 38.4, 34.8,26.6, 23.0, 15.7; LC-MS [M+1]⁺: 445.6

Intermediate 2:(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamidehydrochloride

Intermediate 2 was prepared using exactly the same method as describedin the preparation of Intermediate 1.

Intermediate 3:(2S,4R)-4-hydroxy-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Step 1: Preparation of methyl 3-(benzyloxy) isoxazole-5-carboxylate

To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (7.20 g, 50.31mmol, 1.00 eq) in acetone (150 mL) was added potassium carbonate (13.91g, 100.62 mmol, 2.00 eq). The mixture was heated to 80° C. for 1 hr,then (bromomethyl) benzene (10.33 g, 60.37 mmol, 1.20 eq) was added. Theresulting mixture was stirred at 80° C. for another 3 hr. LC/MS showedthe reaction was completed. The solid was filtered off and the filtratedwas concentrated under vacuum. The residue was further purified bysilica gel column chromatography (petroleum ether:Ethyl acetate=15:1 to10:1) to afford methyl 3-benzyloxyisoxazole-5-carboxylate (9.50 g, 40.73mmol, 81% yield) as a colorless oil. The oil was solidified afterstanding at 15° C. for 15 hr. LC-MS (ESI) m/z: 256.0 [M+Na⁺]; ¹H NMR(400 MHz, CDCl3) δ 7.49-7.41 (m, 5H), 6.60 (s, 1H), 5.34 (s, 2H), 3.97(s, 3H).

Step 2: Preparation of (3-(benzyloxy)isoxazol-5-yl)methanol

To a solution of methyl 3-benzyloxyisoxazole-5-carboxylate (2.33 g, 9.99mmol, 1.00 eq) in methanol (50 mL) was added sodium borohydride (756 mg,19.98 mmol, 2.00 eq) in portions. The resulting mixture was stirred at15° C. for 3 hr. TLC (petroleum ether:ethyl acetate=5:1) showed thereaction was completed. The mixture was poured into hydrochloric acid(0.2 M, 200 mL), and extracted with ethyl acetate (150 mL×2). Thecombined organic layers were washed with saturated brine (200 mL×2),dried over anhydrous sodium sulfate, filtered and concentrated in vacuumto afford (3-benzyloxyisoxazol-5-yl)methanol (1.85 g, 9.02 mmol, 90%yield) as colorless oil. LC-MS (ESI) m/z: 206.1 [M+H⁺].

Step 3: Preparation of 2-(3-(benzyloxy) isoxazol-5-yl)acetonitrile

To a solution of cyanic bromide (334 mg, 3.15 mmol, 1.05 eq) andtriphenylphosphine (787 mg, 3.00 mmol, 1.00 eq) in dichloromethane (10mL) was added a solution of (3-benzyloxyisoxazol-5-yl)methanol (616 mg,3.00 mmol, 1.00 eq) in dichloromethane (10 mL). The mixture was stirredat 15° C. for 1 hour, then 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (480 mg, 3.15 mmol, 1.05 eq) was added at 0° C. Theresulting mixture was stirred at 0° C. for another 14 hr. LC-MS showedthe reaction was completed. The solvent was concentrated under vacuum.The residue was further purified by silica gel column chromatography(petroleum ether:ethyl acetate=5:1 to 4:1) to afford2-(3-benzyloxyisoxazol-5-yl)acetonitrile (320 mg, 1.49 mmol, 50% yield)as a colorless oil. LC-MS (ESI) m/z: 215.0 [M+H⁺]; ¹H NMR (400 MHz,CDCl₃) δ 7.48-7.41 (m, 5H), 6.06 (s, 1H), 5.30 (s, 2H), 3.82 (s, 2H).

Step 4: Preparation of 2-(3-(benzyloxy)isoxazol-5-yl)-3-methylbutanenitrile

To a solution of 2-(3-benzyloxyisoxazol-5-yl)acetonitrile (214 mg, 1.00mmol, 1.00 eq) in N,N-dimethylformamide (3 mL) was added potassiumcarbonate (138 mg, 1.00 mmol, 1.00 eq). The mixture was stirred at 15°C. for half an hour, then 2-iodopropane (170 mg, 1.00 mmol, 1.00 eq) wasadded. The resulting mixture was stirred at 15° C. for another 2.5 hr.LC-MS showed no reaction. Then potassium 2-methylpropan-2-olate (90 mg,0.8 mmol, 0.80 eq) was added to the mixture, the mixture was stirred at15° C. for another 12 hr. TLC (petroleum ether:ethyl acetate=3:1) showedthe reaction was almost complete. The mixture was poured intohydrochloric acid (0.2 M, 30 mL), extracted with ethyl acetate (30mL×2). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel column chromatography (petroleum ether:ethylacetate=10:1 to 8:1) to afford2-(3-benzyloxyisoxazol-5-yl)-3-methyl-butanenitrile (150 mg, 0.56 mmol,59% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.41 (m,5H), 6.04 (s, 1H), 5.28 (s, 2H), 3.85 (d, J=5.6 Hz, 1H), 2.42-2.37 (m,1H), 1.18 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

Step 5: Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid

To a solution of 2-(3-benzyloxyisoxazol-5-yl)-3-methyl-butanenitrile(3.40 g, 13.27 mmol, 1.00 eq) in dioxane (30 mL) was added hydrochloricacid (11.8 M, 120 mL). The mixture was heated to 100° C. and stirred at100° C. for 15 hr. LC/MS showed the reaction was complete. The mixturewas cooled to 15° C., and extracted with ethyl acetate (150 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude product was furtherpurified by preparative HPLC (column: Daiso 150×25 mm, 5 micron; mobilephase: [water (0.225% TFA)-ACN] to afford2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoic acid (230 mg, 1.19 mmol, 9%yield) as a yellow solid. LC-MS (ESI) m/z: 186.1 [M+H⁺].

Step 6: Preparation of(2S,4R)-4-hydroxy-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

To a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoic acid (185mg, 1.00 mmol, 1.00 eq) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (570 mg, 1.50 mmol, 1.50 eq) inN,N-dimethylformamide (5 mL) was added diisopropylethylamine (645 mg,5.0 mmol, 5.00 eq). The mixture was stirred at 15° C. for half an hour,then(2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(353 mg, 1.0 mmol, 1.00 eq, hydrochloride salt) was added. The resultingmixture was stirred at 15° C. for another 14.5 hr. The mixture waspoured into saturated brine (50 mL), and extracted with ethyl acetate(30 mL×2). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was furtherpurified by preparative HPLC (Phenomenex Synergi C18 150×25 mm, 10micron; mobile phase: [water(0.225% FA)-ACN] to afford(2S,4R)-4-hydroxy-1-[2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoyl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(220 mg, 0.45 mmol, 46% yield) as an off-white solid. LC-MS (ESI) m/z:485.1 [M+H⁺].

Compound 111:(2S,4R)-1-((S)-2-tert-butyl-14-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Step 1: Preparation of3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene-1-oxide

A mixture of 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (2 g,6.23 mmol) and trifluoroacetic acid (20 ml) in dichloromethane (20 mL)was stirred at 0° C. for 5 minutes, followed by addition of aqueoushydrogen peroxide (30%, 862 mg, 7.47 mmol). After stirring at 0° C. foradditional 30 minutes, the resulting mixture was allowed to warm up toroom temperature and stirred at room temperature for 3 hours. TLC showedformation of desired product. Solid sodium bisulfite (392 mg, 3.11 mmol)was added cautiously to the dark solution followed by water (3 mL). Theresulting mixture was stirred at room temperature for 15 minutes. Thevolatiles were removed under reduced pressure, the residue waspartitioned between dichloromethane (150 mL) and water (80 mL), theorganic phase was washed with aqueous sodium bicarbonate (1N, 50 mL) andbrine (50 mL), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a crude residue which was purified bysilica gel flash chromatography (eluted with 0-4% ethyl acetate indichloromethane) to afford3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene 1-oxide (620 mg,yield 30%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 3.93 (s, 3H),7.13-7.16 (m, 1H), 7.19-7.23 (m, 2H), 7.49-7.50 (m, 1H), 7.56-7.58 (m,1H), 7.79-7.82 (m, 2H).

Step 2: Preparation of2-(4-fluorophenyl)-6-methoxy-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenoxy)benzo[b]thiophene-1-oxide

To a stirred solution of 4-(tetrahydro-2H-pyran-2-yloxy)phenol (303 mg,1.56 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added sodiumhydride (60% in mineral oil, 113 mg, 2.83 mmol) in portions at 0° C.After stirring at 0° C. for 10 minutes,3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene-1-oxide (500 mg,1.42 mmol) was added, the resulting mixture was allowed to warm up toroom temperature and stirred at room temperature for 2 hours. TLC showedformation of desired product. The reaction mixture was carefullyquenched with water (25 mL) at 0° C. and extracted with ethyl acetate(30 mL×3). The combined organic layer was washed with water (30 mL) andbrine (30 mL), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a crude residue which was purified bysilica gel flash chromatography (eluted with 0-4% ethyl acetate indichloromethane) to afford2-(4-fluorophenyl)-6-methoxy-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenoxy)benzo[b]thiophene-1-oxide(500 mg, yield 75%) as yellow oil. LC/MS: (ES⁺): m/z 467.10 [M+H⁺]; ¹HNMR (400 MHz, CDCl₃): δ 1.59-1.70 (m, 3H), 1.82-1.86 (m, 2H), 1.93-2.04(m, 1H), 3.57-3.62 (m, 1H), 3.85-3.91 (m, 4H), 5.29-5.31 (m, 1H),6.90-6.99 (m, 5H), 7.02-7.07 (m, 3H), 7.50 (s, 1H), 7.72-7.75 (m, 2H).

Step 3: Preparation of4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenol

To a stirred solution of2-(4-fluorophenyl)-6-methoxy-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenoxy)benzo[b]thiophene-1-oxide(500 mg, 1.0 mmol) and sodium iodide (804 mg, 5.36 mmol) in acetonitrile(5 mL) was added chlorotrimethylsilane (349 mg, 3.22 mmol) dropwise atroom temperature, the resulting mixture was stirred at room temperaturefor 30 minutes. TLC showed formation of desired product. The reactionmixture was partitioned between aqueous sodium sulfite solution (1N, 60mL) and ethyl acetate (150 mL). The organic layer was collected, washedwith water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash chromatography (eluted with 0-4%ethyl acetate in dichloromethane) to afford4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenol (350 mg,yield 89%) as white solid. LC/MS: (ES⁺): m/z 366.90 [M+H⁺]; ¹H NMR (400MHz, CDCl₃): δ 3.87 (s, 3H), 4.55 (s, 1H), 6.70-6.73 (m, 2H), 6.82-6.89(m, 3H), 7.02-7.06 (m, 2H), 7.25-7.29 (m, 2H), 7.69-7.72 (m, 2H).

Step 4: Preparation of tert-butyl2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenol (350 mg,1.00 mmol), tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate(418 mg, 1.00 mmol) and potassium carbonate (414 mg, 3.00 mmol) inacetonitrile (10 mL) was stirred at refluxing temperature overnight. TLCshowed formation of desired product. The reaction mixture was cooled toroom temperature, partitioned between ethyl acetate (120 mL) and water(50 mL). The organic layer was collected, washed with brine (50 mL),dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a crude residue which was purified by silica gel flashchromatography (eluted with 0-5% ethyl acetate in dichloromethane) toafford tert-butyl2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(500 mg, yield 85%) as lightless oil. LC/MS: (ES⁺): m/z 635.10 [M+Na⁺];¹H NMR (400 MHz, CDCl₃): δ1.46 (s, 9H), 3.66-3.73 (m, 8H), 3.81-3.83 (m,2H), 3.87 (s, 3H), 4.01 (m, 2H), 4.04-4.07 (m, 2H), 6.78-6.82 (m, 2H),6.85-6.89 (m, 3H), 7.02-7.06 (m, 2H), 7.25-7.27 (m, 2H), 7.68-7.72 (m,2H).

Step 5: Preparation of2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid

A mixture of tert-butyl2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(440 mg, 0.72 mmol) and lithium chloride (610 mg, 14.38 mmol) in dry1-methylpyrrolidin-2-one (4 mL) was stirred at 220° C. for 3 hours.LC/MS showed formation of the desired product. The reaction mixture wascooled to room temperature and directly purified by preparative HPLC toafford2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (200 mg, yield 51%) as brown oil. LC/MS: (ES⁺): m/z 543.20 [M+H⁺].

Step 6: Preparation of (2S,4R)-1-((S)-2-tert-butyl-14-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

To a stirred solution of2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (130 mg, 0.24 mmol),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloric acid salt (200 mg, crude), andN-ethyl-N-isopropylpropan-2-amine (124 mg, 0.96 mmol) in anhydrousN,N-dimethylformamide (2 mL) was added HATU(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (230 mg, 0.60 mmol) at 0° C., the resulting mixturewas allowed to warm up to room temperature and stirred at roomtemperature for 30 min. TLC showed formation of desired product. Thereaction mixture was partitioned between ethyl acetate (150 mL) andwater (50 mL). The organic layer was collected, washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a crude residue which was purified by preparative HPLCto afford(2S,4R)-1-((S)-2-tert-butyl-14-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(25 mg, yield 11%) as white solid. LC/MS: (ES⁺): m/z 969.30 [M+H⁺]; ¹HNMR (400 MHz, CD₃OD): δ 1.03 (s, 9H), 1.49 (d, J=6.8 Hz, 3H), 1.92-1.99(m, 1H), 2.18-2.23 (m, 1H), 2.48, 2.49 (two singles, 3H), 3.70-3.75 (m,9H), 3.81-3.86 (m, 3H), 4.03-4.09 (m, 4H), 4.43 (br, 1H), 4.55-4.59 (m,1H), 4.68 (br, 1H), 4.97-5.02 (m, 1H), 6.78-6.81 (m, 1H), 6.85-6.87 (m,4H), 7.07-7.12 (m, 2H), 7.18-7.20 (m, 2H), 7.38-7.45 (m, 4H), 7.12-7.76(m, 2H), 8.88 and 8.89 (two singles, 1H).

Compound 112:(2S,4R)-1-((S)-2-(2-(3-(3-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)propoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Compound 112 was prepared using the same method as described forCompound 111. ¹H NMR (400 MHz, CD₃OD):δ 1.03, 1.04 (two singles, 9H),1.48-1.58 (m, 3H), 1.87-2.03 (m, 5H), 2.19-2.24 (m, 1H), 2.47, 2.49 (twosingles, 3H), 3.57-3.65 (m, 6H), 3.76-4.02 (m, 6H), 4.45 (br, 1H),4.55-4.71 (m, 2H), 4.97-5.02 (m, 1H), 6.79-6.87 (m, 5H), 7.08-7.20 (m,4H), 7.40-7.46 (m, 4H), 7.72-7.76 (m, 2H), 8.87, 8.89 (two singles, 1H).LC/MS: (ES⁺): m/z 953.30 [M+H⁺].

Compound 113:(2S,4R)-1-((S)-2-(2-(2-(3-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)propoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Compound 113 was prepared using the same method as described forCompound 111. ¹H NMR (400 MHz, CD₃OD):δ 1.02 (s, 9H), 1.46-1.57 (m, 3H),1.96-2.05 (m, 3H), 2.17-2.23 (m, 1H), 2.47 (s, 3H), 3.66-3.76 (m, 7H),3.83-3.86 (m, 1H), 3.99-4.08 (m, 4H), 4.44 (br, 1H), 4.55-4.59 (m, 1H),4.68-4.69 (m, 1H), 4.97-4.99 (m, 1H), 6.78-6.80 (m, 1H), 6.84, 6.86 (twosingles, 4H), 7.07-7.11 (m, 2H), 7.18-7.20 (m, 2H), 7.38-7.44 (m, 4H),7.64-7.76 (m, 3H), 8.88 and 8.89 (two singles, 1H). LC/MS: (ES⁺): m/z939.30 [M+H⁺].

Compound 140:(2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideStep 1: Preparation of 3-bromo-2-(4-bromophenyl)-1-benzothiophen-6-ol

To a 3-necked round-bottom flask purged and maintained with nitrogen,was placed a solution of3-bromo-2-(4-bromophenyl)-6-methoxy-1-benzothiophene (3.2 g, 7.99 mmol,1.00 equiv) in dichloromethane (50 mL). Then boron tribromide (1M indichloromethane) (50 mL, 5.00 equiv) was added dropwise with stirring atroom temperature. The resulting solution was stirred for 1 hour at roomtemperature. The reaction was then quenched by the addition of water.The resulting solution was extracted with dichloromethane (100 mL×2),and the organic layers were combined. The resulting mixture was washedwith brine. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 3.0 g (crude) of3-bromo-2-(4-bromophenyl)-1-benzothiophen-6-ol as a brown solid. LC/-MS(ES⁺): m/z 383.86/385.86 [M+H⁺].

Step 2: Preparation of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)benzo[b]thiophene

Into a 100-mL round-bottom flask purged and maintained with nitrogen,was placed a solution of 3-bromo-2-(4-bromophenyl)-1-benzothiophen-6-ol(3.0 g, 7.85 mmol, 1.00 equiv), sodium hydride (471.2 mg, 11.78 mmol,1.50 equiv) in N,N-dimethylformamide (20 mL). The resulting solution wasstirred for 10 minutes at room temperature. Then (bromomethyl)benzene(1.5 g, 8.64 mmol, 1.1 equiv) was added dropwise at room temperature.The resulting solution was stirred for 1 hour at room temperature. Thereaction was then quenched by the addition of water (150 mL). The solidswere filtered and the crude product was purified by re-crystallizationfrom ethyl acetate. This resulted in 3.5 g (96%) of6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-benzo[b]thiophene as a whitesolid. LC-MS (ES⁺): m/z 473.91/475.91 [M+H⁺].

Step 3: Preparation of6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-benzothiophen-1-one

Into a 100-mL round-bottom flask, was placed a solution of6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-1-benzothiophene (2.5 g, 5.27mmol, 1.0 equiv) in trifluoroacetic acid (10 mL) and dichloromethane (10mL). Then hydrogen peroxide (0.5 mL, 1.20 equiv, 33% aq) was addeddropwise at room temperature. The resulting solution was stirred for 5hours at room temperature. The resulting solution was extracted withdichloromethane (100 mL×2), and the organic layers were combined. Theresulting mixture was washed with brine. The mixture was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The crude product was purified byre-crystallization from ethyl acetate. This resulted in 2.2 g (85%) of6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-1-benzothiophen-1-one as ayellow solid. LC-MS (ES⁺): m/z 489.91/491.91 [M+H⁺].

Step 4: Preparation of6-(benzyloxy)-2-(4-bromophenyl)-3-[4-(oxan-2-yloxy)phenoxy]-benzothiophen-1-one

To a round bottom flask was placed a solution of6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-benzothiophen-1-one (1.2 g, 2.45mmol, 1.00 equiv), sodium hydride (147.0 mg, 6.12 mmol, 1.50 equiv) inN, N-dimethylformamide (20 mL). The resulting solution was stirred for10 minutes at room temperature. Then 4-(oxan-2-yloxy) phenol (570.0 mg,2.93 mmol, 1.20 equiv) was added. The resulting solution was stirred for1 hour at room temperature. The reaction was then quenched by theaddition of water. The resulting solution was extracted with ethylacetate (100 mL×2), and the organic layers were combined. The resultingmixture was washed with brine. The mixture was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 1.5 g (crude) of6-(benzyloxy)-2-(4-bromophenyl)-3-[4-(oxan-2-yloxy)phenoxy]benzothiophen-1-oneas yellow oil. LC/MS (ES⁺): m/z 604.95/606.95 [M+H⁺].

Step 5: Preparation of4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy] phenol

To a solution of6-(benzyloxy)-2-(4-bromophenyl)-3-[4-(oxan-2-yloxy)phenoxy]-benzothiophen-1-one(1.5 g, 2.49 mmol, 1.00 equiv) in acetonitrile (20 mL) was addedtrimethylchlorosilane (540 mg, 4.97 mmol, 2.00 equiv) and sodium iodide(1.1 g, 3.00 equiv). The resulting solution was stirred for 5 minutes atroom temperature. The reaction was then quenched by the addition ofsaturated sodium thiosulfate solution. The resulting solution wasextracted with ethyl acetate (20 mL×2), and the organic layers werecombined. The resulting mixture was washed with brine. The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column eluted with ethyl acetate/petroleum ether(v:v=1:2). This resulted in 800.0 mg (64%) of4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenol as ayellow solid. ¹H NMR (400 MHz, CD₃OD): δ 7.62 (d, J=6.4 Hz, 2H), 7.35(m, 9H), 6.95 (m, 1H), 6.80 (m, 2H), 6.70 (m, 2H), 5.15 (d, J=14.2 Hz,2H); LC-MS (ES⁺): m/z 504.95 [M+H⁺].

Step 6: Preparation of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate

Into a 1000-mL round-bottom flask, was placed 2-(benzyloxy)ethan-1-ol(10.0 g, 65.71 mmol, 1.00 equiv), tert-butyl 2-bromoacetate (19.2 g,98.43 mmol, 1.50 equiv), dichloromethane (150 mL), 37% sodium hydroxide(150 mL), and tetrabutylammonium chloride (18.3 g, 65.83 mmol, 1.00equiv). The resulting solution was stirred for 4 h at room temperaturein a water/ice bath. The resulting solution was extracted withdichloromethane (100 mL×3) and the organic layers were combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluted with ethyl acetate/petroleum ether (1/15). This resultedin 15.0 g (86%) of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate as yellowoil.

Step 7: Preparation of tert-butyl 2-(2-hydroxyethoxy)acetate

Into a a solution of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate (20.9 g,78.47 mmol, 1.00 equiv) in methanol (250 mL) was added palladium oncarbon (15.0 g, 92.02 mmol, 10.00 equiv). The solution was degassed andstirred under hydrogen for 16 h. The resulting mixture was filtered andthe filtrate was concentrated under vacuum. This resulted in 9.9 g (72%)of tert-butyl 2-(2-hydroxyethoxy)acetate as a light yellow solid.

Step 8: Preparation of tert-butyl2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)acetate

To a solution of tert-butyl 2-(2-hydroxyethoxy)acetate (4.5 g, 25.54mmol, 1.00 equiv) in dichloromethane (50 mL) was added triethylamine(5.2 g, 51.39 mmol, 2.01 equiv), 4-methylbenzene-1-sulfonyl chloride(5.8 g, 30.42 mmol, 1.20 equiv) and catalytic amount of4-dimethylaminopyridine. The resulting solution was stirred for 8 h atroom temperature. The reaction was then quenched by the addition ofwater (100 mL). The resulting solution was extracted withdichloromethane (30 mL×3) and the organic layers were combined. Theresulting mixture was washed with brine (20 mL×1). The mixture was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column eluted with ethyl acetate/petroleumether (1:3). This resulted in 6.1 g (72%) of tert-butyl2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)acetate as colorless oil.LC/MS (ES⁺): m/z 275.06 [M+H⁺-Bu^(t)].

Step 9: Preparation of tert-butyl4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylate

Into a 250-mL 3-necked round-bottom flask purged with nitrogen, wasplaced a solution of4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenol (6.4g, 12.71 mmol, 1.00 equiv) in methylbenzene (120 mL). To this solutionwas added tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.9 g,25.62 mmol, 2.00 equiv), triphenylphosphine (5.0 g, 19.06 mmol, 1.50equiv), and diethyl azodicarboxylate (3.3 g, 18.95 mmol, 1.50 equiv).The resulting solution was stirred for 4 h at 110° C. in an oil bath.The reaction was then quenched by the addition of water/ice (100 mL).The resulting solution was extracted with ethyl acetate (80 mL×3) andthe organic layers were combined. The resulting mixture was washed withbrine (50 mL×1). The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a C18 reversephase column eluted with methanol/water (3:5). The collected fractionswere combined and concentrated under vacuum. This resulted in 4.0 g(44%) of tert-butyl4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylateas a yellow solid. LC/MS (ES⁺): 716.95/718.95 [M+H⁺].

Step 10: Preparation of1-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazinehydrochloride

To a solution of tert-butyl4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylate(4.0 g, 5.59 mmol, 1.00 equiv) in methanol (30 mL) was added hydrogenchloride in dioxane (4N, 5 mL). The resulting solution was stirred for16 h at room temperature. The resulting mixture was concentrated undervacuum. This resulted in 3.3 g (91%) of1-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazinehydrochloride as a yellow solid.

Step 11: Preparation of tert-butyl2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-benzylkoxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetate

To a solution of1-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazinehydrochloride (5.6 g, 8.59 mmol, 1.00 equiv) in N,N-dimethylformamide(80 mL) was added potassium carbonate (2.4 g, 17.36 mmol, 2.00 equiv),tert-butyl 2-(2-[(4-methylbenzene)sulfonyl]oxyethoxy)acetate (3.7 g,11.20 mmol, 1.30 equiv), and sodium iodide (430.0 mg, 4.30 mmol, 0.50equiv). The resulting mixture was stirred for 12 h at 80° C. in an oilbath. The reaction was then quenched by the addition of water/ice (50mL×1). The resulting solution was extracted with ethyl acetate (50 mL×3)and the organic layers were combined. The resulting mixture was washedwith brine (30 mL×1). The mixture was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column eluted with ethyl acetate/petroleum ether (2:1) toprovide 5.3 g (90%) of tert-butyl2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-benzyloxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetateas a yellow solid. LC-MS (ES⁺): m/z 773.20/775.20 [M+H⁺].

Step 12: Preparation of2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)aceticacid

To a stirred solution of tert-butyl2-(2-[4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetate(5.1 g, 6.59 mmol, 1.00 equiv) in dichloromethane (30 mL) was addedboron tribromide in dichloromethane (1N, 30.0 mL) dropwised at −78° C.The resulting solution was stirred for 2 h at −78° C. The reaction wasthen quenched by the addition of water (50 mL). The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn eluted with acetonitrile in water (40%). The collected fractionswere combined and concentrated under vacuum. This resulted in 3.7 g(89%) of2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)aceticacid as a crude yellow solid. LC-MS (ES⁺): m/z 626.90/628.90 [M+H⁺].This solid was further purified by reverse phase preparative HPLC.

Step 13: Preparation of(2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)aceticacid (500.0 mg, 0.80 mmol) in N,N-dimethylformamide (10 mL) was added(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(445.0 mg, 1.03 mmol, 1.20 equiv), (benzotriazole-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (353.0 mg, 0.80 mmol,1.00 equiv), and ethyldiisopropylamine (0.5 mL) at 0° C. The resultingsolution was stirred for 1 h at room temperature. The reaction was thenquenched by the addition of water (100 mL). The resulting solution wasextracted with ethyl acetate (100 mL×3) and the organic layers werecombined. The resulting mixture was washed with brine (20 mL×2). Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The crude product was purified by preparative HPLC with thefollowing conditions: column, Gemini-NX C18 AXAI Packed, 21.2×150 mm, 5um; mobile phase, water (10 mmol/L ammonium bicarbonate) andacetonitrile (hold 54.0% acetonitrile in 16 min); Detector, uv 220 nm.This resulted in 207.1 mg (25%) of(2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 7.63-7.61 (d,J=8.4 Hz, 2H), 7.48-7.46 (d, J=8.4 Hz, 2H), 7.44-7.41 (m, 2H), 7.39-7.36(m, 2H), 7.19-7.18 (m, 2H), 6.83-6.76 (m, 5H), 4.68 (s, 1H), 4.53-4.50(m, 3H), 4.31-4.30 (m, 1H), 4.04-3.98 (m, 4H), 3.97-3.94 (m, 2H),3.69-3.67 (m, 2H), 2.74-2.65 (m, 12H), 2.67 (s, 3H), 2.36-2.22 (m, 1H),2.12-2.01 (m, 1H), 1.00 (m, 9H). LC-MS (ES⁺): m/z 1041.25/1043.25 [MH⁺].

Compound 118:(2S,4R)-1-((S)-2-(2-(2-(4-(2-(4-((2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Compound 118 was prepared using the same method as described in Compound140. ¹H NMR (400 MHz, CD₃OD): δ 1.02, 1.05 (two singles, 9H), 2.07-2.12(m, 1H), 2.21-2.27 (m, 1H), 2.47, 2.48 (two singles, 3H), 2.94-3.22 (m,12H), 3.80-3.88 (m, 4H), 4.07-4.18 (m, 4H), 4.34-4.38 (m, 1H), 4.50-4.55(m, 3H), 4.70 (br, 1H), 6.78-6.86 (m, 5H), 7.07-7.12 (m, 2H), 7.17-7.18(m, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.39-7.45 (m, 4H), 7.72-7.76 (m, 2H),8.87, 8.88 (two singles, 1H). LC/MS: (ES⁺): m/z 979.30 [M+H⁺].

Compound 151:(2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-chlorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Compound 151 was prepared using the same method as described forCompound 140. ¹H NMR (300 MHz, CD₃OD): δ 8.818 (s, 1H), 7.69-7.66 (m,2H), 7.50-7.30 (m, 6H), 7.18-7.14 (m, 2H), 6.83-6.75 (m, 5H), 4.79 (s,1H), 4.67-4.48 (m, 4H), 4.31-4.26 (m, 1H), 4.08-3.98 (m, 4H), 3.93-3.80(m, 2H), 3.79-3.75 (m, 2H), 2.90-2.61 (m, 11H), 2.43 (s, 3H), 2.19-2.11(m, 1H), 2.10-2.06 (m, 1H), 1.01 (s, 9H); LC-MS (ES⁺): m/z 995.30/997.30[M+H⁺].

Compound 153:(2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Compound 153 was prepared using the same method as described forCompound 140. Briefly, to a solution of2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)aceticacid (50.0 mg, 0.08 mmol, step 12 for Compound 140) inN,N-dimethylformamide (10 mL) was added(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamidehydrochloride (47.0 mg, 0.10 mmol, 1.20 equiv),(benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (43.0 mg, 0.10 mmol, 1.20 equiv), andN,N-diisopropylethylamine (41.0 mg, 0.32 mmol, 4.00 equiv). Theresulting solution was stirred for 1 h at room temperature. The reactionwas then quenched by the addition of water (10 mL). The resultingsolution was extracted with ethyl acetate (15 mL×3) and the organiclayers were combined. The resulting mixture was washed with brine (10mL×1). The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude material was purified bypreparative HPLC to give 26.0 mg (31%) of(2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.90-8.80 (s, 1H),7.64-7.61 (m, 2H), 7.49-7.46 (m 2H), 7.43-7.36 (m, 4H), 7.19-7.17 (m,2H), 6.86-6.83 (m, 4H), 6.79-6.76 (m, 1H), 4.99-4.97 (m, 1H), 4.67 (s,1H), 4.60-4.52 (m, 1H), 4.40 (m, 1H), 4.12-4.05 (m, 4H), 3.90-3.75 (m,4H), 3.10-2.85 (m, 12H), 2.46-2.45 (2s, 3H), 2.25-2.15 (m, 1H),2.00-1.95 (m, 1H), 1.55 and 1.50 (2d, 3H), 1.01 (s, 9H); LC-MS (ES⁺):m/z 1055.45/1057.45 [M+H⁺].

Compound 121:(2S,4R)-1-[(2S)-2-[2-(4-[1-[2-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]-1H-pyrazol-3-yl]phenyl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of2-(4-[1-[2-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]-1H-pyrazol-3-yl]phenyl)aceticacid (40.0 mg, 0.07 mmol, 1.00 equiv, prepared according to Scheme 9A)in N,N-dimethylformamide (5.0 mL), and(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride (39.0 mg, 0.08 mmol, 1.20 equiv) was added. This wasfollowed by the addition of(benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (37.0 mg, 0.08 mmol, 1.20 equiv) andN-ethyl-N-isopropylpropan-2-amine (0.3 ml) at 10° C. The resultingsolution was stirred for 1 h at room temperature. The reaction was thenquenched by the addition of water (20 mL). The resulting solution wasextracted with ethyl acetate (20 mL×3) and the organic layers werecombined. The resulting mixture was washed with brine (10 mL×1). Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum then purified by preparative HPLC under the following condition:Column, X Bridge C18, 19×250 mm, 5 um; Mobile Phase A: water/110 mmol/Lammonium bicarbonate, Mobile Phase B: acetonitrile; Flow rate: 20mL/min; Gradient: 10% B to 80% B in 12 min; detected at 254 nm. Thisresulted in 15.4 mg (23%) of(2S,4R)-1-[(2S)-2-[2-(4-[1-[2-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]-1H-pyrazol-3-yl]phenyl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD): δ 9.01 (s, 1H), 7.71-7.68 (m,5H), 7.48-7.42 (m, 4H), 7.40-7.36 (m, 2H), 7.34-7.10 (m, 4H), 6.78-6.76(m, 5H), 6.58-6.58 (m, 1H), 4.64 (s, 1H), 4.62-4.60 (m, 5H), 4.38-4.30(m, 3H), 3.87-3.80 (m, 1H), 3.77-3.70 (m, 1H), 3.65-3.63 (m, 2H), 2.47(s, 3H), 2.19-2.06 (m, 1H), 2.06-1.98 (m, 1H), 0.99 (s, 9H); LC-MS(ES⁺): m/z 993.05 [MH⁺].

Compound 142:(2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Step 1: Preparation of 1-(4-fluorophenyl)-2-[(3-methoxyphenyl)sulfanyl]ethan-1-one

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of potassium hydroxide(15.6 g, 278.03 mmol, 10.00 equiv), 3-methoxybenzene-1-thiol (35.6 g,253.92 mmol, 1.00 equiv) in water (100 mL), ethanol (250 mL). This wasfollowed by the addition of a solution of2-bromo-1-(4-fluorophenyl)ethan-1-one (50.0 g, 230.38 mmol, 1.00 equiv)in ethyl acetate (80 mL) dropwise with stirring at 0° C. over 30minutes. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Thesolids were filtered out. The mixture was dried over anhydrous sodiumsulfate. The residue was applied onto a silica gel column eluted withethyl acetate/petroleum ether (v:v=1:10). This resulted in 133 g (80%)of 1-(4-fluorophenyl)-2-[(3-methoxyphenyl)sulfanyl]ethan-1-one as yellowoil. LC/MS (ESI) m/z: 276.95 [M+1]⁺.

Step 2: Preparation of 2-(4-fluorophenyl)-6-methoxy-1-benzothiophene

Into a 500-mL round-bottom flask, was placed a solution of1-(4-fluorophenyl)-2-[(3-methoxyphenyl)sulfanyl]ethan-1-one (111.7 g,404.23 mmol, 1.00 equiv) in PPA (950 g). The resulting solution wasstirred overnight at 130° C. Then the mixture was cooled, poured intoice/water and adjusted pH to 7 by sodium carbonate. The solids werecollected by filtration. The solid was dried in an oven under reducedpressure. This resulted in 37.6 g (36%) of2-(4-fluorophenyl)-6-methoxy-1-benzothiophene as a brown solid. ¹H NMR(300 MHz, DMSO) δ 7.77 (m, 4H), 7.56 (s, 1H), 7.33 (t, J=3.0 Hz, 2H),7.02 (d, J=2.4 Hz, 1H), 3.83 (s, 3H).

Step 3: Preparation of3-bromo-2-(4-fluorophenyl)-6-methoxy-1-benzothiophene

Into a 1000-mL round bottom flask was placed a solution of2-(4-fluorophenyl)-6-methoxy-1-benzothiophene (17.0 g, 65.81 mmol, 1.00equiv), N-bromoacetamide (9.1 g, 65.96 mmol, 1.01 equiv) indichloromethane (420 mL). The resulting solution was stirred for 2 hoursat room temperature. The resulting solution was extracted with ethylacetate (500 mL×2), and the organic layers were combined. The resultingmixture was washed with brine. The mixture was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (v:v=1:100). This resulted in42.2 g (95%) of 3-bromo-2-(4-fluorophenyl)-6-methoxy-1-benzothiophene asa gray solid. LC/MS (ESI) m/z: 336.85 [M+1]⁺.

Step 4: Preparation of 3-bromo-2-(4-fluorophenyl)-1-benzothiophen-6-ol

Into a 250-mL round-bottom flask, was placed a solution of3-bromo-2-(4-fluorophenyl)-6-methoxy-1-benzothiophene (5.1 g, 15.12mmol, 1.00 equiv) in dichloromethane (15 mL, 3.00 equiv). To this wasadded tribromoborane (2 M in dichloromethane, 20 mL) dropwise at roomtemperature. The resulting solution was stirred for 2 hours at roomtemperature. The reaction was then quenched by the addition of water.The resulting solution was extracted with dichloromethane (100 mL×2),and the organic layers were combined. The resulting mixture was washedwith brine. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 4.8 g (98%) of3-bromo-2-(4-fluorophenyl)-1-benzothiophen-6-ol as a white solid.

Step 5: Preparation of6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-1-benzothiophene

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of3-bromo-2-(4-fluorophenyl)-1-benzothiophen-6-ol (4.8 g, 14.85 mmol, 1.00equiv), sodium hydride (890.0 mg, 37.08 mmol, 1.50 equiv) in N,N-dimethylformamide (100 mL). The resulting solution was stirred for 10minutes at room temperature. Then (bromomethyl)benzene (3.8 g, 22.22mmol, 1.50 equiv) was added dropwise with stirring for 2 hours at roomtemperature. The reaction was then quenched by the addition of water.The solids were collected by filtration. The crude product was purifiedby re-crystallization from ethyl acetate. This resulted in 5.6 g (91%)of 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-1-benzothiophene as a whitesolid. ¹H-NMR (400 MHz, CDCl₃) δ 7.77 (m, 3H), 7.45 (m, 6H), 7.17 (m,3H), 5.25 (s, 2H).

Step 6: Preparation of6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-benzothiophen-1-one

Into a 1000-mL round-bottom flask, was placed a solution of6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-1-benzothiophene (20.0 g, 48.39mmol, 1.00 equiv), trifluoroacetic acid (200 mL), dichloromethane (200mL). Then H₂O₂ (30%, 11.3 mL, 3.00 equiv) was added dropwise at 0° C.The resulting solution was stirred for 3 hours at room temperature. Thereaction was then quenched by the addition of sodium sulfite. Theresulting solution was extracted with dichloromethane (500 mL×2) and theorganic layers were combined and dried over anhydrous sodium sulfate.The solids were filtered out. The resulting mixture was concentratedunder vacuum. The crude product was purified by re-crystallization fromethyl acetate, which resulted in 15.5 g (75%) of6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-benzothiophen-1-one as a yellowsolid. LC/MS (ESI) m/z: 428.90 [M+1]⁺.

Step 7: Preparation of6-(benzyloxy)-3-(4-bromophenoxy)-2-(4-fluorophenyl)-benzothiophen-1-one

Into a 100-mL round-bottom flask, was placed 4-bromophenol (725.9 mg,4.20 mmol, 1.00 equiv),6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-benzothiophen-1-one (1.8 g,4.19 mmol, 1.00 equiv), potassium carbonate (1.7 g, 12.30 mmol, 3.00equiv), N,N-dimethylformamide (15 mL). The resulting solution was firststirred for 3 hours at 70° C. in an oil bath and then stirred for 10minutes at room temperature. The reaction was quenched with water (50mL), extracted with ethyl acetate (50 mL×2), washed with water (50 mL)and brine (50 mL), dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column elutedwith ethyl acetate/petroleum ether (v:v=1:8). This resulted in 1.7 g(78%) of6-(benzyloxy)-3-(4-bromophenoxy)-2-(4-fluorophenyl)-benzothiophen-1-oneas a yellow solid. LC/MS (ESI) m/z: 520.75 [M+1]⁺.

Step 8: Preparation of tert-butyl4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate

Into a 25-mL round-bottom flask, was placed6-(benzyloxy)-3-(4-bromophenoxy)-2-(4-fluorophenyl)-1-benzothiophene(50.0 mg, 0.10 mmol, 1.00 equiv), tert-butyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(61.2 mg, 0.20 mmol, 2.00 equiv), potassium carbonate (41.0 mg, 0.30mmol, 3.00 equiv), ethylene glycol dimethyl ether (2 mL), water (0.5mL), tetrakis(triphenylphosphine)palladium (22.9 mg, 0.02 mmol, 0.05equiv). The resulting solution was stirred for 2 hours at 100° C. in anoil bath. The mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column eluted with ethyl acetate/petroleumether (v:v=1:5). This resulted in 40.0 mg (67%) of tert-butyl4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylateas yellow oil. LC/MS (ESI) m/z: 608.15 [M+1]⁺.

Step 9: Preparation of4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridine

Into a 25-mL round-bottom flask, was placed tert-butyl4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate(250.0 mg, 0.41 mmol, 1.00 equiv) and hydrogen chloride/dioxane (5 mL).The resulting solution was stirred for 2 hours at room temperature. Themixture was concentrated under vacuum. This resulted in 230.0 mg (crude)of4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridineas yellow oil. LC/MS (ESI) m/z: 508.05 [M+1]⁺.

Step 10a: Preparation of tert-butyl [2-(2-hydroxyethoxy)ethoxy]acetate

To a cold and stirred solution of diethylene glycol (3 eq) in anhydrousN,N-dimethylformamide [amount of di-alcohol (g)×5 mL] was added sodiumhydride (60%, 1.2 eq) in portions at 0° C. under nitrogen atmosphere.The reaction mixture was allowed to warm to room temperature and stirredat room temperature for 1 hour, then re-cooled to 0° C., and tert-butyl2-bromoacetate (1 eq) was added in portions. The resulting mixture wasallowed to warm up to room temperature and stirred at room temperaturefor 2 hours. The reaction was carefully quenched with water (amount ofdi-alcohol×10 mL) under ice-water cooling and extracted with methylenedichloride. The combined organic phase was washed with brine, dried overanhydrous magnesium sulfate and evaporated to dryness under reducedpressure. The crude product was purified by silica gel chromatography(eluent 1-6% methanol in methylene dichloride) to afford the desiredproduct as colorless oil (yield 46%). ¹H-NMR (400 MHz, CDCl₃) δ 4.03 (s,2H), 3.62-3.76 (m, 8H), 2.46 (br, 1H), 1.48 (s, 9H).

Step 10b: Preparation of tert-butyl2-(2-[2-[4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethoxy]ethoxy)acetate

Into a 50-mL round-bottom flask, was placed4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridine(230.0 mg, 0.45 mmol, 1.00 equiv), tert-butyl2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]acetate (169.3 g,452.13 mmol, 1.00 equiv), potassium carbonate (187.4 g, 1.36 mol, 3.00equiv), N,N-dimethylformamide (5 mL). The resulting solution was stirredfor 3 hours at 70° C. in an oil bath. The mixture was diluted with water(15 mL), extracted with ethyl acetate (20 mL×3), washed with brine (20mL×2), dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluted withdichloromethane/methanol (v:v=10:1). This resulted in 200.0 mg (62%) oftert-butyl2-(2-[2-[4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethoxy]ethoxy)acetateas yellow oil. LC/MS (ESI) m/z: 710.15 [M+1]⁺.

Step 11: Preparation of tert-butyl2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetate

Into a 50-mL round-bottom flask, was placed tert-butyl2-(2-[2-[4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethoxy]ethoxy)acetate(200.0 mg, 0.28 mmol, 1.00 equiv), methanol (5 mL), palladium on carbon(150.0 mg). Then hydrogen was introduced in. The resulting solution wasstirred for 3 hours at room temperature. The solids were filtered out.The resulting mixture was concentrated under vacuum. This resulted in150.0 mg (86%) of tert-butyl2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetateas yellow oil. LC/MS (ESI) m/z: 622.15 [M+1]⁺.

Step 12: Preparation of2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)aceticacid

Into a 20-mL round-bottom flask, was placed tert-butyl2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetate(150.0 mg, 0.24 mmol, 1.00 equiv), dichloromethane (1 mL),trifluoroacetic acid (1 mL). The resulting solution was stirred for 2hours at room temperature. The resulting mixture was concentrated undervacuum. This resulted in 120.0 mg (88%) of2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)aceticacid as yellow oil. LC/MS (ESI) m/z: 566.25 [M+1]⁺.

Step 13: Preparation of(2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide(Compound 142)

Into a 50-mL round-bottom flask, was placed a solution of2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)aceticacid (100.0 mg, 0.18 mmol, 1.00 equiv),(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide(78.5 mg, 0.18 mmol, 1.00 equiv),(benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (94.0 mg, 1.20 equiv), N,N-diisopropylethylamine(68.5 mg, 0.53 mmol, 3.00 equiv) in N,N-dimethylformamide (1 mL). Theresulting solution was stirred for 10 minutes at 0° C. The reaction wasthen quenched by the addition of water. The mixture was extracted withethyl acetate (20 mL×2), and the organic layers were combined. Thesolution was washed with brine, dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting solution was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column; 5 um, 19×150 mm;mobile phase, water with 0.05% trifluoroacetic acid andacetonitrile/methanol=1/1; Detector, UV 254 nm. This resulted in 38.0 mg(22%) of(2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamideas a white solid. LC/MS (ESI) m/z: 992.40 [M+1]⁺; ¹H-NMR (400 MHz,CD₃OD) δ 8.87 (s, 1H), 7.72 (m, 3H), 7.40 (m, 4H), 7.15 (m, 6H), 6.92(m, 1H), 6.79 (m, 1H), 4.97 (m, 1H), 4.72 (m, 1H), 4.55 (m, 1H), 4.30(m, 1H), 4.09 (m, 2H), 3.89 (m, 2H), 3.74 (m, 7H), 3.45 (m, 3H), 3.18(m, 2H), 2.89 (m, 1H), 2.45 (s, 3H), 2.22 (m, 1H), 2.11 (m, 2H), 1.95(m, 3H), 1.45 (m, 3H), 1.05 (s, 9H).

Compound 147:(2S,4R)—N-[(1S)-1-(4-cyanophenyl)ethyl]-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamideStep 1: Preparation of tert-butylN-[(2S)-1-[(2S,4R)-2-{[(1S)-1-(4-cyanophenyl)ethyl]carbamoyl}-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

To a solution containing(2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1.75 g, 5.10 mmol) and (S)-4-(1-aminoethyl)benzonitrilehydrochloride (933.0 mg, 5.10 mmol) in DMF (10.00 ml) at roomtemperature was added TBTU (2.45 g, 7.64 mmol) and DIPEA (2.70 mL, 15.6mmol). The mixture was stirred for 2 hours and then quenched with waterand extracted with EtOAc. The mixture was washed with water (3×), brine(2×), filtered through a Biotage Universal Phase Separator and thenconcentrated in vacuum. The crude material was purified by silica gelchromatography on a Teledyne Combiflash ISCO eluting with MeOH/DCM(0:100 to 7:93) to yield tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(4-cyanophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(2.02 g, 4.27 mmol, 83.8%). LC/MS (ESI) m/z: 473.21 [M+1]⁺; ¹H-NMR (400MHz, CDCl₃) δ 7.72 (d, J=4.7 Hz, 1H), 7.64 (dd, J=3.5, 8.2 Hz, 2H), 7.42(dd, J=3.5, 8.2 Hz, 2H), 5.20 (d, J=8.6 Hz, 1H), 5.05 (dt, J=3.5, 7.0Hz, 1H), 4.79 (dt, J=3.1, 7.8 Hz, 1H), 4.50 (br. s., 1H), 4.12-4.23 (m,2H), 3.55 (d, J=11.3 Hz, 1H), 2.52-2.62 (m, 1H), 2.03-2.12 (m, 1H), 1.68(br. s., 1H), 1.39-1.47 (m, 12H), 1.05 (d, J=3.5 Hz, 9H).

Step 2: Preparation of(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(1S)-1-(4-cyanophenyl)ethyl]-4-hydroxypyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(4-cyanophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(2.03 g, 4.29 mmol) in hydrogen chloride solution (4 M) in dioxane (5.93mL, 171 mmol) was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure to give a whitesolid. The material was diluted with toluene and concentrated severaltimes and then placed on the high vacuum for 30 minutes to yield an offwhite solid as(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N—((S)-1-(4-cyanophenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamidehydrochloride (1.60 g, 3.91 mmol, 91.4%). LC/MS (ESI) m/z: 411.24[M+1]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (d, J=5.9 Hz, 1H), 8.04 (br. s.,3H), 7.54 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.93-5.04 (m, 2H),4.56 (br. s., 1H), 4.46 (d, J=4.3 Hz, 1H), 4.09 (d, J=11.7 Hz, 1H), 3.59(d, J=11.0 Hz, 1H), 2.24 (dd, J=7.6, 13.1 Hz, 1H), 1.93-2.04 (m, 1H),1.53 (d, J=7.0 Hz, 3H), 1.29 (s, 9H).

Step 3: Preparation of(2S,4R)—N-[(1S)-1-(4-cyanophenyl)ethyl]-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide(147)

Into a 50-mL round-bottom flask, was placed a solution of2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)aceticacid (100.0 mg, 0.18 mmol, 1.00 equiv),(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(1S)-1-(4-cyanophenyl)ethyl]-4-hydroxypyrrolidine-2-carboxamidehydrogen chloride (66.0 mg, 0.18 mmol, 1.00 equiv) inN,N-dimethylformamide (5 mL). Then (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (94.0 mg, 1.20 equiv),N,N-diisopropylethylamine (68.0 mg, 0.53 mmol, 3.00 equiv) were addedinto at 0° C. The reaction was stirred for 4 hours and then quenched bythe addition of water. The resulting solution was extracted with ethylacetate (20 mL×2), and the organic layers were combined. The solutionwas washed with brine. The mixture was dried over anhydrous sodiumsulfate. The solids were filtered out. The filtrate was concentratedunder vacuum. The crude product was purified by preparative HPLC withthe following conditions: Column, XBridge Shield RP18 OBD, 5 um, 19×150mm; mobile phase, water with 0.05% trifluoroacetic acid andacetonitrile/methanol=1/1; Detector, UV 254 nm. This resulted in 35.2 mg(22%) of(2S,4R)—N-[(1S)-1-(4-cyanophenyl)ethyl]-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamideas a white solid. LC/MS (ESI) m/z: 920.35 [M+1]⁺; ¹H-NMR (400 MHz,CD₃OD) δ 7.77 (m, 4H), 7.45 (m, 2H), 7.20 (m, 4H), 7.09 (m, 2H), 6.92(m, 2H), 6.79 (m, 1H), 4.93 (m, 1H), 4.72 (m, 1H), 4.55 (m, 1H), 4.30(m, 1H), 4.09 (m, 2H), 3.89 (m, 2H), 3.74 (m, 7H), 3.45 (m, 3H), 3.18(m, 2H), 2.89 (m, 1H), 2.22 (m, 1H), 2.12 (m, 2H), 1.90 (m, 3H), 1.45(m, 3H), 1.02 (s, 9H).

Compound 158:(2S,4R)-1-[(2S)-2-[2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Step 1: Preparation of 1-(benzyloxy)-4-[2-(2-bromoethoxy)ethoxy]benzene

Into a 1000-mL round-bottom flask was placed a solution of4-(benzyloxy)phenol (5 g, 24.97 mmol, 1.00 equiv) in tetrahydrofuran(200 mL), 370% NaOH (200 mL), and 1-bromo-2-(2-bromoethoxy)ethane (57.5g, 247.94 mmol, 10.00 equiv). The resulting solution was stirredovernight at 70° C. in an oil bath. The reaction mixture was cooled. Theresulting solution was extracted with dichloromethane and the organiclayers were combined. The solution was dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel column (ethyl acetate/petroleum ether) to afford1-(benzyloxy)-4-[2-(2-bromoethoxy)ethoxy]benzene (6.67 g, 76%) as awhite solid. LC/MS (ESI) m/z: 350.05 [M+1]⁺.

Step 2: Preparation of tert-butyl4-(2-[2-[4-(benzyloxy)phenoxy]ethoxy]ethyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of1-(benzyloxy)-4-[2-(2-bromoethoxy)ethoxy]benzene (2 g, 5.69 mmol, 1.00equiv) in acetonitrile (100 mL), tert-butyl piperazine-1-carboxylate(1.79 g, 9.61 mmol, 1.20 equiv), potassium carbonate (3.31 g, 23.95mmol, 3.00 equiv), and KI (0.0664 g, 0.05 equiv). The resulting mixturewas stirred for 16 hours at 80° C. in an oil bath and then filtered andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluted with dichloromethane/methanol (10:1) to afford tert-butyl4-(2-[2-[4-(benzyloxy)phenoxy]ethoxy]ethyl)piperazine-1-carboxylate(2.48 g, 95%) as yellow oil. LC/MS (ESI) m/z: 456.26 [M+1]⁺.

Step 3: Preparation of tert-butyl4-[2-[2-(4-hydroxyphenoxy)ethoxy]ethyl]piperazine-1-carboxylate

To a solution of tert-butyl4-(2-[2-[4-(benzyloxy)phenoxy]ethoxy]ethyl)piperazine-1-carboxylate(2.48 g, 5.43 mmol, 1.00 equiv) in 50 mL MeOH was added Pd/C (10%, 1.0g) under nitrogen atmosphere in a 100 ml round bottom flask. The flaskwas degassed and flushed with hydrogen. The reaction mixture washydrogenated at 40° C. for 16 hours under hydrogen atmosphere using ahydrogen balloon, then filtered through a Celite pad and concentratedunder reduced pressure. The residue was applied onto a silica gel columneluted with dichloromethane/methanol (10:1) to afford tert-butyl4-[2-[2-(4-hydroxyphenoxy)ethoxy]ethyl]piperazine-1-carboxylate (1.6 g,80%) as a off-white solid. LC/MS (ESI) m/z: 366.22 [M+1]⁺.

Step 4: Preparation of tert-butyl4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-oxo-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine-1-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl4-[2-[2-(4-hydroxyphenoxy)ethoxy]ethyl]piperazine-1-carboxylate (500 mg,1.36 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL). This wasfollowed by the addition of sodium hydride (56.6 mg, 2.36 mmol, 2.30equiv) and the mixture was stirred at 0° C. for 30 minutes. To thismixture was added6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-benzothiophen-1-one (450 mg,0.92 mmol, 1.20 equiv). The resulting solution was stirred for 16 hoursat room temperature and then diluted with ethyl acetate. The mixture waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gel column(dichloromethane/methanol=10/1 to 8/1) to afford tert-butyl4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-oxo-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine-1-carboxylate(916 mg, 87%) as yellow crude oil. LC/MS (ESI) m/z: 774.20 [M+1]⁺.

Step 5: Preparation of tert-butyl4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylate

Into a 100-mL round-bottom flask, was placed tert-butyl4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-oxo-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylate(916 mg, 1.25 mmol, 1.00 equiv), NaI (1882.5 mg, 10.00 equiv), TMSCl(406.6 mg, 3.74 mmol, 3.00 equiv) in 40 mL of acetonitrile. The mixturewas stirred for 16 hours at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gel column(dichloromethane/methanol=(10/1 to 8/1) to affordtert-butyl4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylate(147 mg, 16%) as yellow oil. LC/MS (ESI) m/z: 758.20 [M+1]⁺.

Step 6: Preparation of1-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine-1-carboxylate(147 mg, 0.19 mmol, 1.00 equiv) in dichloromethane (10 mL) andtrifluoroacetic acid (3 mL). The resulting solution was stirred for 1hour at room temperature. The resulting mixture was concentrated undervacuum. This resulted in1-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine;2,2,2-trifluoroacetaldehyde (920 mg) as yellow crude oil. LC/MS (ESI)m/z: 658.15 [M+1]⁺.

Step 7: Preparation of tert-butyl2-(4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetate

Into a 100-mL round-bottom flask, was placed a solution of1-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazinein acetonitrile (20 mL), DIEA (2.0 mL), and tert-butyl 2-bromoacetate(619.1 mg, 3.17 mmol, 3.00 equiv). The resulting solution was stirredfor 3 h at room temperature and then evaporated. The residue was dilutedwith dichloromethane and washed with brine. The mixture was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was applied onto a silica gel column eluted with ethylacetate/petroleum ether. This resulted in tert-butyl2-(4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetate(280 mg, 39%) as yellow oil. LC/MS (ESI) m/z: 772.22 [M+1]⁺.

Step 8: Preparation of2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)aceticacid

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl2-(4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetate(266 mg, 0.34 mmol, 1.00 equiv) in dichloromethane (30 mL). This wasfollowed by the addition of BBr₃ (10 mL) dropwise with stirring at −70°C. The resulting solution was stirred for 4 h at −70° C. The reactionwas then quenched by the addition of water. The resulting mixture wasconcentrated under vacuum. The crude product was purified by preparativeHPLC and resulted in2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)aceticacid (147 mg, 68%) as yellow oil. LC/MS (ESI) m/z: 626.11 [M+1]⁺.

Step 9: Preparation of(2S,4R)-1-[(2S)-2-[2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Compound 158)

Into a 50-mL round-bottom flask, was placed a solution of2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)aceticacid (50 mg, 0.08 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL). Tothis solution was added(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(37.3 mg, 0.09 mmol, 1.00 equiv), BOP (35.3 mg, 1.00 equiv), and DIEA (2mL). The mixture was stirred for 1 hour at 0° C. in a water/ice bath.The resulting solution was diluted with ethyl acetate and washed withbrine. The solution was dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The crude product was purified bypreparative HPLC with the following conditions: Column, XSelect CSH PrepC18 OBD, 5 um, 19×150 mm; mobile phase, water (0.1% formic acid) andacetonitrile (32.0% to 52.0% acetonitrile in 8 min); Detector, UV 254nm. This resulted in(2S,4R)-1-[(2S)-2-[2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(31.3 mg, 38%) as a white solid. LC/MS (ESI) m/z: 1038.30/1040.30[M+1]⁺; ¹H-NMR (300 MHz, CD₃OD) δ 8.862 (s, 1H), 8.323 (s, 1H),7.64-7.60 (m, 2H), 7.49-7.37 (m, 5H), 7.18-7.15 (m, 2H), 6.83-6.75 (m,5H), 4.63-4.31 (m, 5H), 4.08-4.05 (m, 2H), 3.85-3.78 (m, 5H), 3.18-3.07(m, 7H), 2.71-2.62 (m, 3H), 2.45-2.40 (m, 3H), 2.29-2.03 (m, 2H),1.28-1.27 (m, 1H), 1.01-0.99 (m, 9H).

Compound 164:(2S,4R)-1-((S)-2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl4-[2-(4-benzyloxyphenoxy)ethyl]piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate(1.00 g, 4.02 mmol, 1.00 eq), 4-benzyloxyphenol (965 mg, 4.82 mmol, 1.20eq) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.57 g,4.82 mmol, 1.20 eq) and potassium iodide (66 mg, 0.4 mmol, 0.10 eq)under nitrogen. The reaction was stirred at 80° C. for 10 hours. TLC(Petroleum ether/Ethyl acetate=3/1) and LC/MS showed most of thestarting material was consumed. Water (100 mL) was added to the mixture,and the resulting mixture was extracted with ethyl acetate (50 mL×3).The combined organic phase was washed with brine (80 mL), dried oversodium sulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=50/1 to 3/1) to provide tert-butyl4-[2-(4-benzyloxyphenoxy)ethyl]piperazine-1-carboxylate (1.4 g, 3.39mmol, 84% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.29(m, 5H), 6.95-6.88 (m, 2H), 6.88-6.81 (m, 2H), 5.02 (s, 2H), 4.07 (t,J=5.8 Hz, 2H), 3.51-3.42 (m, 4H), 2.80 (t, J=5.8 Hz, 2H), 2.56-2.48 (m,4H), 1.47 (s, 9H).

Step 2: Preparation of tert-butyl 4-[2-(4-hydroxyphenoxy)ethyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[2-(4-benzyloxyphenoxy)ethyl]piperazine-1-carboxylate (1.40 g, 3.39mmol, 1.00 eq) in methanol (20 mL) was added palladium on carbon (200mg, 10% purity) under nitrogen. The suspension was degassed under vacuumand purged with hydrogen several times. The mixture was stirred underhydrogen (50 psi) at 20° C. for 4 hours. TLC (petroleum ether/ethylacetate=1/1) showed most of the starting material was consumed. Thereaction mixture was filtered and the filtrate was evaporated and driedunder vacuum to provide tert-butyl4-[2-(4-hydroxyphenoxy)ethyl]piperazine-1-carboxylate (1 g, 3.07 mmol,90% yield, 99% purity as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ6.74 (s, 4H), 4.04 (t, J=5.6 Hz, 2H), 3.54-3.38 (m, 5H), 2.79 (t, J=5.6Hz, 2H), 2.53 (s, 4H), 1.46 (s, 9H).

Step 3: Preparation of tert-butyl 4-(2-(4-((2-(4-bromophenyl)-6-methoxy-1-oxidobenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazine-1-carboxylate

To a solution of tert-butyl4-[2-(4-hydroxyphenoxy)ethyl]piperazine-1-carboxylate (234 mg, 0.72mmol, 1.00 eq) in N,N-dimethylformamide (5 mL) was added NaH (29 mg,0.72 mmol, 60% mineral oil, 1.00 eq) at 0° C. The mixture was stirred at20° C. for 0.5 hour. Then3-bromo-2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium (300 mg,0.72 mmol, 1.00 eq) was added, and the mixture was stirred at 20° C. for1 hour. LC/MS showed the reaction was completed and desired MS can bedetected. The reaction mixture was quenched with water (10 mL) andextracted with ethyl acetate (10 mL×3). The combined organic phase waswashed with brine (10 mL×2), dried over anhydrous sodium sulfate,filtered and concentrated in vacuum to afford tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate(430 mg, 0.66 mmol, 90% yield) as a yellow solid, which was directlyused for next step without further purification. LC/MS (ESI) m/z: 657.5[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J=8.4 Hz, 2H), 7.52-7.46 (m,3H), 7.05-6.89 (m, 4H), 6.81 (d, J=8.4 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H),3.89 (s, 3H), 3.50-3.42 (m, 4H), 2.81 (t, J=5.6 Hz, 2H), 2.52 (s, 4H),1.47 (s, 9H).

Step 4: Preparation of tert-butyl4-(2-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazine-1-carboxylate

To a solution of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxido-benzothiophen-1-ium-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate(370 mg, 0.56 mmol, 1.00 eq) in acetonitrile (6 mL) was added sodiumiodide (254 mg, 1.69 mmol, 3.00 eq) and trimethylchlorosilane (123 mg,1.13 mmol, 2.00 eq). The mixture was stirred at 20° C. for 1 hour. LC/MSshowed the reaction was completed and desired MS was detected. Thereaction mixture was quenched with saturated sodium sulfite (2 mL),diluted with water (15 mL) and extracted with ethyl acetate (10 mL×2).The combined organic phase was washed with brine (10 mL×2), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum to givethe crude product tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate (350 mg, crude) as a yellow oil, which wasdirectly used for next step without further purification. LC/MS (ESI)m/z: 639.0 [M+1]⁺.

Step 5: Preparation of 2-(4-bromophenyl)-3-(4-(2-(piperazin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-6-ol

To a solution of tert-butyl4-[2-[4-[2-(4-bromophenyl)-6-methoxy-benzothiophen-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate (350 mg, 0.55 mmol, 1.00 eq)in dichloromethane (6 mL) was added boron tribromide (410 mg, 1.64 mmol,0.16 mL, 3.00 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour.The reaction mixture was quenched with saturated sodium bicarbonate (5mL) at 0° C., diluted with water (10 mL) and extracted withdichloromethane (10 mL×3). The combined organic phase was washed withbrine (5 mL×2), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum to give2-(4-bromophenyl)-3-[4-(2-piperazin-1-ylethoxy)phenoxy]benzothiophen-6-ol(250 mg, crude) as a yellow solid, which was directly used for next stepwithout further purification. LC/MS (ESI) m/z: 527.0 [M+1]⁺; ¹H NMR (400MHz, DMSO) δ 7.65-7.56 (m, 4H), 7.31 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.4Hz, 1H), 6.86 (s, 4H), 6.83 (dd, J=2.0, 8.4 Hz, 1H), 5.75 (s, 1H), 3.97(t, J=5.6 Hz, 2H), 2.78-2.66 (m, 4H), 2.61 (t, J=5.6 Hz, 2H), 2.40 (s,4H), 2.45-2.34 (m, 1H).

Step 6: Preparation of(2S,4R)-1-(2-(3-(2,2-dimethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

To a solution of(2S,4R)-4-hydroxy-1-[2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoyl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(220 mg, 0.45 mmol, 1.00 eq) and 2-bromo-1,1-dimethoxy-ethane (153 mg,0.91 mmol, 2.00 eq) in N,N-dimethylformamide (5 mL) was added cesiumcarbonate (296 mg, 0.91 mmol, 2.00 eq). The mixture was stirred at 100°C. for 3 hours. The mixture was poured into brine (50 mL), and thenextracted with ethyl acetate (50 mL×2). The combined organic layers werewashed with brine (50 mL×3), dried over anhydrous sodium sulfate,filtered and concentrated in vacuum to afford(2S,4R)-1-[2-[3-(2,2-dimethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(220 mg, crude) as a yellow oil, which was directly used for next stepwithout further purification. LC/MS (ESI) m/z: 573.2 [M+1]⁺.

Step 7: Preparation of(2S,4R)-4-hydroxy-1-(3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

To a solution of(2S,4R)-1-[2-[3-(2,2-dimethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(200 mg, 0.35 mmol, 1.00 eq) in dioxane (2 mL) was added hydrochloricacid (2.0 M, 2 mL). The mixture was stirred at 50° C. for 3 hours. Themixture was diluted with brine (30 mL), adjusted the pH to 7.0˜8.0 withsodium carbonate solid, and then extracted with ethyl acetate (30 mL×5).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuum to afford(2S,4R)-4-hydroxy-1-[3-methyl-2-[3-(2-oxoethoxy)isoxazol-5-yl]butanoyl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(160 mg, crude) as a yellow oil, which was directly used for next stepwithout further purification. LC/MS (ESI) m/z: 527.1 [M+1]⁺.

Step 8: Preparation of(2S,4R)-1-(2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

To a solution of(2S,4R)-4-hydroxy-1-[3-methyl-2-[3-(2-oxoethoxy)isoxazol-5-yl]butanoyl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(160 mg, 0.30 mmol, 1.00 eq) and2-(4-bromophenyl)-3-[4-(2-piperazin-1-ylethoxy)phenoxy]benzothiophen-6-ol(184 mg, 0.30 mmol, 1.00 eq, hydrobromide salt) in methanol (5 mL) wasadded acetic acid (5 mg, 0.06 mmol, 0.20 eq). The mixture was stirred at20° C. for 1 hour. Then sodium cyanoborohydride (38 mg, 0.60 mmol, 2.00eq) was added. The resulting mixture was stirred at 20° C. for another14 hours. The resulting solution was poured into saturated sodiumbicarbonate solution (50 mL), and then extracted with ethyl acetate (50mL×2). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby preparative HPLC (Phenomenex Synergi C18 150×25 mm, 10 um; mobilephase: [water (0.05% HCl)-ACN]; B %: 35%-55%, 7.8 min) to afford(2S,4R)-1-(2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(85 mg, 0.08 mmol, 27% yield) as an off-white solid. LC/MS (ESI) m/z:1037.1 [M+1]⁺.

Step 9: Preparation of(2S,4R)-1-((S)-2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Compound 164)

(2S,4R)-1-[2-[3-[2-[4-[2-[4-[2-(4-bromophenyl)-6-hydroxy-benzothiophen-3-yl]oxyphenoxy]ethyl]piperazin-1-yl]ethoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(85 mg, 0.08 mmol, 1.00 eq) was separated by SFC (column: OD, 250 mm×50mm, 10 um); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 60%-60%, 3.3 min eachrun, 70 min total) to afford(2S,4R)-1-[(2R)-2-[3-[2-[4-[2-[4-[2-(4-bromophenyl)-6-hydroxy-benzothiophen-3-yl]oxyphenoxy]ethyl]piperazin-1-yl]ethoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(19 mg, 0.018 mmol, 56% yield, 99% purity) and(2S,4R)-1-[(2S)-2-[3-[2-[4-[2-[4-[2-(4-bromophenyl)-6-hydroxy-benzothiophen-3-yl]oxyphenoxy]ethyl]piperazin-1-yl]ethoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(50 mg, 0.46 mmol, 93% yield, 96% purity) as a yellow solid. LC/MS (ESI)m/z: 1037.3 [M+1]⁺; ¹H-NMR for Compound 164 (400 MHz, CD₃OD) δ 8.89 (s,1H), 7.64 (d, J=8.8 Hz, 2H), 7.51-7.48 (m, 6H), 7.22-7.19 (m, 2H),6.92-6.79 (m, 5H), 6.05 (s, 1H), 4.60-4.42 (m, 6H), 3.90-3.68 (m, 5H),3.20-2.74 (m, 12H), 2.49 (s, 3H), 2.48-2.45 (m, 1H), 2.38-2.35 (m, 1H),2.10-2.08 (m, 1H), 1.05 (d, J=7.2 Hz, 3H), 0.90 (d, J=7.2 Hz, 3H).

Compound 232:3-[5-[4-[[1-[5-[2-(4-fluorophenyl)-6-hydroxy-benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

Step 1: Preparation of 5-benzyloxy-2-bromo-pyridine

To a solution of 6-bromopyridin-3-ol (2 g, 11.49 mmol, 1 eq) inN,N-dimethylformamide (20 mL) was added potassium carbonate (3.18 g,22.99 mmol, 2 eq) and benzyl bromide (2.16 g, 12.64 mmol, 1.5 mL, 1.1eq). The mixture was stirred at 20° C. for 2 hours. Thin layerchromatography (petroleum ether:ethyl acetate=3:1) indicated thestarting material was consumed completely and one new spot formed. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(30 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=1:0 to 50:1). Compound5-benzyloxy-2-bromo-pyridine (2.6 g, 9.84 mmol, 86% yield) was obtainedas a white solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.14 (d, J=3.2 Hz, 1H),7.46-7.31 (m, 6H), 7.16 (dd, J=3.2, 8.8 Hz, 1H), 5.10 (s, 2H).

Step 2: Preparation of5-benzyloxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine

To a solution containing 5-benzyloxy-2-bromo-pyridine (2.4 g, 9.09 mmol,1 eq), 4-(dimethoxymethyl)piperidine (2.67 g, 13.63 mmol, 1.5 eq, HCl)in toluene (20 mL) was added sodium tert-butoxide (2.62 g, 27.26 mmol, 3eq), XPhos (866 mg, 1.82 mmol, 0.2 eq) and palladium acetate (306 mg,1.36 mmol, 0.15 eq) under nitrogen. The reaction mixture was stirred at90° C. for 16 hours. Thin layer chromatography (petroleum ether:ethylacetate=3:1) indicated the starting material was consumed completely andone new spot was formed. The reaction mixture was filtered and thefiltrate was concentrated. Water (50 mL) was poured into the mixture andstirred for 1 minute. The aqueous phase was extracted with ethyl acetate(30 mL×3). The combined organic phase was washed with brine (50 mL×2),dried over anhydrous sodium sulfate, filtered and concentrated invacuum. The crude product was triturated with dichloromethane andmethanol (10/1, 50 mL x 2). Compound5-benzyloxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (2.95 g, 8.61mmol, 95% yield) was confirmed by ¹H NMR as a yellow solid. ¹H NMR (400MHz, CDCl₃-d) δ: 7.98 (d, J=2.8 Hz, 1H), 7.49-7.29 (m, 5H), 7.18 (dd,J=3.2, 9.2 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 5.02 (s, 2H), 4.06 (d, J=6.8Hz, 1H), 3.67 (s, 6H), 2.79-2.66 (m, 2H), 1.95-1.64 (m, 5H), 1.45-1.33(m, 2H).

Step 3: Preparation of 6-[4-(dimethoxymethyl)-1-piperidyl]pyridin-3-ol

To a solution of 5-benzyloxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine(3 g, 8.76 mmol, 1 eq) in methanol (15 mL) was added palladium (10%) onactivated carbon catalyst (300 mg). The mixture was stirred at 20° C.for 12 h under hydrogen (15 psi). The reaction mixture was filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (petroleum ether:ethyl acetate=20:1 to 3:1).The desired compound 6-[4-(dimethoxymethyl)-1-piperidyl]pyridin-3-ol(1.54 g, 6.10 mmol, 70% yield) was obtained as a light yellow solid.¹H-NMR (400 MHz, CDCl₃-d) δ 7.83 (d, J=2.8 Hz, 1H), 7.11 (dd, J=3.2, 9.2Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 4.12-4.00 (m, 3H), 3.37 (s, 6H), 2.72(dt, J=2.0, 12.4 Hz, 2H), 1.91-1.71 (m, 3H), 1.47-1.30 (m, 2H).

Step 4: Preparation of5-[6-benzyloxy-2-(4-fluorophenyl)-1-oxido-benzothiophen-1-ium-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine

To a solution of 6-[4-(dimethoxymethyl)-1-piperidyl]pyridin-3-ol (176mg, 0.70 mmol, 1 eq) in N,N-dimethylformamide (8 mL) was added sodiumhydride (34 mg, 0.84 mmol, 60% in mineral oil, 1.2 eq) at 0° C. Themixture was stirred at 0° C. for 0.5 hour, then to the mixture was added6-benzyloxy-3-bromo-2-(4-fluorophenyl)-1-oxido-benzothiophen-1-ium (300mg, 0.70 mmol, 1 eq). The reaction mixture was stirred at 20° C. for 1hour. The reaction was quenched by addition of saturated ammoniumchloride solution (10 mL) at 20° C., and then diluted with water 10 mLand extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine (30 mL×2), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=20/1 to 3/1). The desired compound5-[6-benzyloxy-2-(4-fluorophenyl)-1-oxido-benzothiophen-1-ium-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine(350 mg, 0.58 mmol, 83% yield) was obtained as a light yellow solid.

Step 5: Preparation of5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine

To a solution of5-[6-benzyloxy-2-(4-fluorophenyl)-1-oxido-benzothiophen-1-ium-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine(350 mg, 0.58 mmol, 1 eq) in acetonitrile (4 mL) was addedtrimethylchlorosilane (190 mg, 1.75 mmol, 3 eq) and sodium iodide (262mg, 1.75 mmol, 3 eq). The mixture was stirred at 20° C. for 1 hour andquenched with water. The reaction mixture was extracted with ethylacetate (20 mL×2). The combined organic layers were first washed withanhydrous sodium sulfite (40 mL), then washed with brine (40 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The product was taken to the next step without furtherpurification. The desired compound5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine(320 mg, 0.55 mmol, 94% yield) was obtained as a light yellow oil. LC/MS(ESI) m/z: 585.1 [M+1]⁺.

Step 6: Preparation of1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]piperidine-4-carbaldehyde

To a solution of5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine(320 mg, 0.55 mmol, 1 eq) in tetrahydrofuran (11 mL) was added sulfuricacid (2 M, 11 mL, 40 eq). The reaction mixture was stirred at 70° C. for0.5 hour. LC-MS showed the starting material was consumed completely andone main peak with desired MS was detected. The reaction mixture wasquenched by addition of saturated sodium bicarbonate solution to adjustpH to 7-8, and extracted with ethyl acetate (30 mL×2). The combinedorganic layers were washed with brine (30 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The productwas taken to the next step without further purification. The desiredcompound1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]piperidine-4-carbaldehyde(270 mg, 0.5 mmol, 92% yield) was obtained as a light yellow oil. LC/MS(ESI) m/z: 539.1 [M+1]⁺.

Step 7: Preparation of3-[5-[4-[[1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (176 mg,0.48 mmol, 1 eq, HCl salt) in dichloromethane (2 mL) and methyl alcohol(2 mL) was added sodium acetate (158 mg, 1.93 mmol, 4 eq). The mixturewas stirred at 20° C. for 0.5 h. Then to the mixture was added1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]piperidine-4-carbaldehyde(260 mg, 0.48 mmol, 1 eq). The mixture was stirred at 20° C. for 0.5hour followed by the addition of sodium cyanoborohydride (60 mg, 0.97mmol, 2 eq). The reaction mixture was stirred at 20° C. for 2 hours.LC-MS showed the starting material was consumed completely and one mainpeak with desired MS was detected. The reaction mixture was concentratedunder reduced pressure. The residue was purified by preparative TLC(DCM:MeOH=10:1). The desired compound3-[5-[4-[[1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(300 mg, 0.32 mmol, 65% yield, 89% purity) was obtained as a whitesolid. LC/MS (ESI) m/z: 851.1[M+1]⁺.

Step 8: Preparation of3-[5-[4-[[1-[5-[2-(4-fluorophenyl)-6-hydroxy-benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Compound 232)

To a solution of3-[5-[4-[[1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(300 mg, 0.31 mmol, 1 eq) in tetrahydrofuran (10 mL) was added palladium(10%) on activated carbon catalyst (30 mg). The reaction mixture wasstirred at 20° C. for 1 hour under hydrogen (15 psi). To the mixture wasadded ethyl alcohol (5 mL), the reaction mixture was stirred at 20° C.under hydrogen (15 psi) for 18 hours. The resulting mixture was filteredand concentrated under reduced pressure. The residue was purified bypreparative HPLC (column: Phenomenex Synergi C18 150×25 mm, 10 um;mobile phase: [water (0.225% formic acid)-ACN]; B %: 18%-38%, 10 min).The desired compound3-[5-[4-[[1-[5-[2-(4-fluorophenyl)-6-hydroxy-benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(126.0 mg, 0.15 mmol, 49% yield, 98% purity, formate) was obtained as awhite solid. LC/MS (ESI) m/z: 761.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d) δ10.94 (s, 1H), 8.14 (s, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.73-7.67 (m, 2H),7.51 (d, J=8.4 Hz, 1H), 7.32-7.19 (m, 4H), 7.11 (dd, J=2.8, 9.2 Hz, 1H),7.08-7.01 (m, 2H), 6.84 (dd, J=2.4, 8.8 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H),5.04 (dd, J=5.2, 13.2 Hz, 1H), 4.37-4.28 (m, 1H), 4.23-4.15 (m, 1H),4.14-4.06 (m, 2H), 3.29-3.21 (m, 7H), 2.96-2.84 (m, 1H), 2.76-2.68 (m,2H), 2.62-2.53 (m, 2H), 2.42-2.29 (m, 1H), 2.22-2.15 (m, 2H), 2.01-1.90(m, 1H), 1.80-1.68 (m, 3H), 1.16-1.00 (m, 2H).

EXAMPLES

All synthesized compounds were characterized by both ¹H-NMR and puritywas analyzed by LC/MS under the wave length of 214 and 254 nM with UVdetection as described below. Purity of each compound in Tables 1-5 wasover 90%. The observed molecular weight from LC/MS in Table 1, Table 2,and Table 3 as [M+H]⁺. The synthetic methods used for preparingindividual compound are also listed in Tables 1-3.

All NMR experiments were recorded either on Bruker Mercury Plus 400 NMRSpectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for protonNMR or on Bruker Mercury Plus 300 NMR Spectrometer equipped with aBruker 300 BBFO probe at 300 MHz for proton NMR. All deuterated solventscontained typically 0.03% to 0.05% v/v tetramethylsilane, which was usedas the reference signal (set at δ 0.00 for both ¹H and ¹³C).

LC-MS analyses were performed on a SHIMADZU LC-MS machine consisting ofan UFLC 20-AD system and LCMS 2020 MS detector. The column used was aShim-pack XR-ODS, 2.2 μm, 3.0×50 mm. A linear gradient was applied,starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05%TFA in acetonitrile) over 2.2 min with a total run time of 3.6 min. Thecolumn temperature was at 40° C. with the flow rate at 1.0 mL/min. TheDiode Array detector was scanned from 200-400 nm. The mass spectrometerwas equipped with an electro spray ion source (ES) operated in apositive or negative mode. The mass spectrometer was scanned between m/z90-900 with a scan time of 0.6 s.

Chimeric molecules were assessed for target engagement in T47D cellsusing the commercial kit of ERE luciferase reporter gene assay. In theassay, 10% FBS was included and estrogen level was measured to be 10 pM.Target engagement was expressed as IC₅₀ in the suppression of estrogeninduced signing and the result was listed in Table 1-3.

Compounds prepared in this application were also analyzed for thedegradation of ERα in MCF7 and T47D cells. FIG. 2 showed the degradationresult with the selected compound and demonstrated the degradationmechanism through cereblon E3 ligase mediated pathway.

ERE Luciferase Assay for Compounds in Table 1-3.

T47D-KBlue cells (ATCC #CRL_2865, T47D human breast cancer cells stablytransfected with estrogen responsive element/promoter/luciferasereporter gene) were seeded into 96-well white opaque plates in RPMIgrowth medium supplemented with 10% fetal bovine serum and allowed toadhere overnight in a 37° C. humidified incubator. The following day,cells were treated with PROTACs in a 12-point concentration curve (topfinal concentration of 300 nM with subsequent concentrations being3-fold less with 2 pM being the lowest concentration in the assay). EachPROTAC was tested independently in two experiments on 96-well plates.After 24 hours, media was removed and lysis buffer was added to thewells. Following lysis, Bright-Go™ Luciferase Assay Substrate (Promega,Madison Wis.) was added and the luciferase activity was measured using aCytation 3 plate reader (TioTek™, Winooski, Vt.). Each compound wasassayed in duplicates and the activity was calculated as IC50 usingGraphPad Prism software (San Diego, Calif.).

Estrogen Receptor-Alpha (ERα) Degradation Assay in MCF-7 Cells UsingWestern Blot Method for Table 4.

The exemplary novel ERα degraders were assessed for their activity indegrading ERα in MCF-7 cells via western blot. The assay was carried outin the presence of 10% fetal bovine serum (FBS) or high percentage ofhuman or mouse serum. Protocols of the western blot assay are describedbelow, which provide comparable results.

MCF7 cells were grown in DMEM/F12 with 10% fetal bovine serum and seededat 24,000 cells per well in 100 μl into 96-well clear tissue cultureplates. The following day, the cells were treated with PROTACs in a7-point concentration curve with 100 nM being the top concentration andserial dilutions to make the other concentrations (30 nM, 10 nM, 3 nM, 1nM, and 0.3 nM). At all concentrations, 0.01% DMSO is the finalconcentration in the well. The following day, the plates are aspirated,washed with 50 μl of cold PBS. The cells are lysed with 50 μl/well 4° C.Cell Lysis Buffer (Catalog #9803; Cell Signaling Technology, Danvers,Mass.) (20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mM Na₂EDTA, 1 mM EGTA,1%; Triton, 2.5 mM sodium pyrophosphate. 1 mM B-glycerophosphate, 1 mMsodium vanadate, 1 ug/ml leupeptin). Lysates were clarified at 16,000×gfor 10 minutes, and 2 μg of protein was subjected to SDS-PAGE analysisand followed by immunoblotting according to standard protocols. Theantibodies used were ERα (Cell Signaling Technologies Catalog #8644),and Tubulin (Sigma Catalog #T9026; St. Louis, Mo.). Detection reagentswere Clarity Western ECL substrate (Bio-Rad Catalog #170-5060; Hercules,Calif.).

Alternatively, MCF7 cells were grown in DMEM/F12 with 10% fetal bovineserum and seeded at 24,000 cells per well in 500 μl in 24-well cleartissue culture plates. The following day, the cells were treated withPROTACs in a 5-point concentration curve (100 nM, 33 nM, 11 nM, 3.7 nM,and 1.2 nM) in the presence of 0.01% DMSO. After 72 hours, the wells areaspirated and washed with 500 μl of PBS. The cells are lysed with 100μl/well 4° C. Cell Lysis Buffer (Catalog #9803; Cell SignalingTechnology, Danvers, Mass.) (20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mMNa₂EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mMB-glycerophosphate, 1 mM sodium vanadate, 1 ug/ml leupeptin). Lysateswere clarified at 16,000×g for 10 minutes, and 2 μg of protein wassubjected to SDS-PAGE analysis and followed by immunoblotting accordingto standard protocols. The antibodies used were ERα (Cell SignalingTechnologies Catalog #8644), and Tubulin (Sigma. Catalog #T9026; St.Louis, Mo.). Detection reagents were Clarity Western ECL substrate(Bio-Rad Catalog #170-5060; Hercules, Calif.).

Estrogen Receptor-Alpha (ERα) Degradation Assay in T47D Cells UsingWestern Blot Method.

The same protocol that was described above with MCF7 cells was utilized,except that T47D cells were utilized instead of the MCF7 cells.

Estrogen Receptor-Alpha (ERα) Degradation Assay Using In-Cell Western™Assay for Table 5.

Degradation of ERα by claimed compounds were determined in MCF7 cellsusing an In-Cell Western™ assay. Briefly, MCF7 cells were plated in96-well plates (2000 cells per well in 100 μl media) and incubated at37° C. under an atmosphere of 5% CO₂ in a humidified incubatorovernight. One-hundred (100) μl of media containing test compound (at 2×concentration) was added to the appropriate wells to provide 11 seriallydecreasing concentrations (top final concentration, 1 μM then 3-foldless for the next 10 concentrations); a vehicle control (DMSO) was alsoadded for each compound. For each experiment, all compounds were assayedon duplicate plates. Cells were then incubated for 3 or 5 days in theabove-mentioned environment. The assay was terminated by removal ofmedia, a single wash with ice-cold PBS and the addition of 50 μlparaformaldehyde (PFA: 4% in PBS). After 15 minutes in PFA at roomtemperature, the cells were permeabilized in Tris-phosphate-bufferedsaline with Tween (0.1%) (TBST) supplemented with Triton X-100 (0.5%)for 15 minutes. Cells were then blocked in BSA (TBST with BSA, 3%) forone hour. Primary antibodies for the detection of ERα (rabbitmonoclonal, 1:1000, Cell Signaling Technology Catalog #8644) and tubulin(mouse monoclonal, 1:5000, Sigma Catalog #T6074) in TBST with BSA (3%)were added. The cells were incubated overnight at 4° C. The cells werethen washed thrice with TBST at room temperature and then incubated withanti-rabbit and anti-mouse fluorescently-labelled secondary antibodies(IRDye©; LI-COR; Lincoln, Nebr.) in LI-COR blocking buffer (Catalog#927-50000) for one hour at room temperature. Following 3 washes withTBST, the buffer was removed and the plates were read on an Odyssey®infrared imaging system (LI-COR®; Lincoln, Nebr.) at 700 nm and 800 nm.Using commercial software (ImageStudio™; LI-COR, Lincoln, Nebr.), thestaining intensity for ERα and tubulin in each well was quantified andexported for analysis. For each data point, ERα intensity was normalizedto tubulin intensity and for each compound all normalized intensityvalues were normalized to the vehicle control. DC₅₀ and D_(max) valueswere determined following a 4-parameter IC₅₀ curve fit using ACAS doseresponse module (McNeil & Co Inc.).

The following PROTACs demonstrated target protein degradation whentested under the conditions described above:

TABLE 1 Activity, characterization and synthetic methods of cerebloncentric benzthiophene derived ER PROTACs ER-α Luciferase *Obsd SyntheticEx. # Structure IC50 (nM) [M + H]⁺ Method 1

12.7 838.1, 840.1 Scheme 14 2

0.36 732.2 Scheme 15 3

0.14 762.2 Scheme 16 4

0.09 748.3 Scheme 15 5

0.9 810.1, 812.2 Scheme 15 6

1.3 824.1, 826.1 Scheme 16 7

1.1 811.2, 813.2 Scheme 17 8

1.9 825.2, 827.0 Scheme 18 9

2.9 888.2, 890.1 Scheme 19 10

0.63 746.2 Scheme 15 11

2.6 852.2, 854.2 Scheme 14 12

2.5 852.2, 854.2 Scheme 14 13

1.3 825.2, 827.2 Scheme 20 14

17.7 837.2, 839.2 Scheme 21 15

1.7 825.2, 827.2 Scheme 20 16

8.8 838.1, 840.2 Scheme 22 17

2.9 743.1, 745.1 Scheme 23 18

81.4 874.2, 876.2 Scheme 23 19

8.9 787.0. 789.1 Scheme 25 20

39.9 888.1, 890.1 Scheme 24 21

17.4 831.1, 833.1 Scheme 25 22

41.4 830.2, 832.2 Scheme 26 23

22.4 844.1, 846.1 Scheme 24 24

16.8 786.1, 788.1 Scheme 26 25

8.6 875.1, 877.2 Scheme 25 26

9.7 800.0, 802.1 Scheme 26 27

8.3 742.2, 744.1 Scheme 26 28

2.7 699.0, 701.0 Scheme 25 29

19.2 756.1, 758.1 Scheme 26 30

1.3 811.2, 813.2 Scheme 17 31

698.1, 700.1 Scheme 26 32

8.2 712.0, 714.0 Scheme 24 33

2.7 743.2, 745.2 Scheme 25 34

1 825.1, 827.1 Scheme 17 35

9.9 771.0, 773.2 Scheme 25 36

4.7 829.2, 831.1 Scheme 25 37

4.2 823.2, 825.2 Scheme 17 38

1.1 823.2, 825.2 Scheme 17 39

3.1 787.0, 789.2 Scheme 25 40

3.9 757.1, 759.0 Scheme 25 41

2.4 823.0, 825.1 Scheme 17 42

0.53 823.1, 825.1 Scheme 17 43

6.1 801.1, 803.3 Scheme 25 44

0.54 826.2, 828.1 Scheme 27 45

6.5 825.2, 817.1 Scheme 25 46

1.9 823.2, 825.2 Scheme 8 47

0.86 851.1, 853.1 Scheme 8 48

8.3 842.8, 844.8 Scheme 25 49

17.7 795.1, 797.1 Scheme 29 50

2.2 822.1, 824.0 Scheme 30 51

26.2 836.8, 838.8 Scheme 29 52

7.4 809.2, 811.2 Scheme 28 53

0.6 837.2, 839.2 Scheme 33 54

12.1 823.2, 825.2 Scheme 28 55

1.8 767.2, 769.2 Scheme 28 56

10.6 781.1, 783.1 Scheme 29 57

3 823.2, 825.2 Scheme 31 58

6.6 795.2, 797.2 Scheme 28 59

3.6 781.2, 783.2 Scheme 28 60

29.9 809.2, 811.2 Scheme 29 61

18.3 823.2, 825.1 Scheme 29 62

8.5 823.2, 825.1 Scheme 29 63

0.82 837.2, 839.2 Scheme 31 64

2.9 823.2, 825.2 Scheme 32 65

2.7 809.2, 811.2 Scheme 32 66

5.8 757.1, 759.1 Scheme 25 67

11.4 799.9, 802.0 Scheme 24 68

5.9 837.2, 839.2 Scheme 32 69

103.3 851.2, 853.2 Scheme 29 70

1.6 838.2, 840.2 Scheme 33 71

0.94 824.2, 826.2 Scheme 15 72

3.1 742.0, 744.0 Scheme 26 73

1.3 824.1, 826.1 Scheme 33 74

11 838.0, 840.0 Scheme 15 75

6.6 756.0, 758.1 Scheme 24 76

17 770.9, 773.0 Scheme 25 77

34.1 807.0, 809.0* Scheme 25 78

28.8 822.8 824.8* Scheme 25 79

27.8 837.0, 839.0* Scheme 25 80

37.4 843.3, 845.1 Scheme 25 81

8.4 770.0, 772.0 Scheme 25 82

32.2 784.0, 786.0 Scheme 24 83

44.9 814.2, 816.1 Scheme 24 84

30.9 842.0, 844.0 Scheme 24 85

6 756.0, 758.0 Scheme 26 86

11 786.1, 788.0 Scheme 26 87

21.5 829.1, 831.0 Scheme 25 88

770.2, 772.3 Scheme 26 89

4.8 814.0, 816.0 Scheme 26 90

Scheme 25 91

Scheme 24 92

Scheme 24 93

Scheme 26 94

Scheme 26 95

Scheme 26 96

Scheme 16 97

Scheme 16 98

Scheme 15 99

Scheme 15 100

Scheme 15 101

Scheme 16 102

Scheme 16 103

104

105

106

107

108

109

110

*Observed [M + Na]⁺ from LC/MS

TABLE 2 Activity, characterization and synthetic methods of VHL centricbenzthiophene derived ER PROTACs IC₅₀ *Obsd Synthetic Ex. # ChemicalStructure (nM) [M + H]⁺ Methods 111

   0.6  969.3 Scheme 2A, 18A 112

   15.8  953.3 Scheme 18A 113

   23.7  939.3 Scheme 18A 114

   22  991.4 Scheme 5A 115

>100 1003.2 Scheme 3A, 5A, 6A 116

   3  980.3 Scheme 7A 117

   3.3  966.2 Scheme 8A 118

   0.4  979.3 Scheme 19A 119

   1.1  985.3 Scheme 18A 120

   4.1  969.3 Scheme 18A 121

   1  993.1 Scheme 9A 122

>100  989.5 Scheme 6A 123

   5.5  980.2 Scheme 7A 124

   2.2 1005.2 Scheme 6A 125

   1.6 1005.2 Scheme 6A 126

   0.2 1031.2 Scheme 18A 127

   0.2 1015.3 Scheme 18A 128

   0.3  982.2 Scheme 10A 129

   1.4  919.3 Scheme 10A 130

   3.5  504.1 (M + 2H)/2 Scheme 9A 131

   0.4  978.3 Scheme 7A 132

   1.3  897.2 Scheme 11A, 18A 133

   3.7  972.3 Scheme 12A 134

   2.6  988.1 Scheme 13A 135

   0.8  978.5 Scheme 14A 136

   1.5  905.3 (M + Na) Scheme 11A 137

   87  978.6 Scheme 7A 138

   0.1  935.3 Scheme 18A 139

   0.6 1000.1 Scheme 10A 140

   11 1039.6 Scheme 19A 141

   1.5 1007.5 Scheme 9A 142

   0.5  992.5 Scheme 14A 143

   32  906.5 Scheme 14A 144

>100  915.4 Scheme 14A 145

   97  921.4 Scheme 9A 146

>100  930.2 Scheme 9A 147

   1  920.4 Scheme 14A 148

>100  929.3 Scheme 14A 149

   1.4  935.4 Scheme 9A 150

   17  944.4 Scheme 9A 151

   0.4  995.3 Scheme 19A 152

>100 1039.4 Scheme 19A 153

   3.2 1053.5 Scheme 19A 154

>100 1053.4 Scheme 1A, 4A, 19A 155

>100 1067.3 Scheme 1A, 4A, 19A 156

>100 1023.3 Scheme 19A 157

>100 1037.4 Scheme 1A, 4A, 19A 158

   13.7 1039.4 Scheme 15A 159

>100 1051.4 Scheme 1A, 4A, 19A 160

   6.3 1065.4 Scheme 16A 161

 972.2 Scheme 20A 162

 972.2 Scheme 20A 163

>100  518.2 (M + 2H)/2 Scheme 20A 164

   2.7  518.3 (M + 2H)/2 Scheme 20A 165

 963.2 Scheme 20A 166

 963.2 Scheme 20A 167

 1053.3 Scheme 19A 168

 536.2 (M + 2H)/2 Scheme 17A, 11A, 19A 169

 1083.2 Scheme 17A, 11A, 19A

TABLE 3 Activity, characterization and synthetic methods of cerebloncentric benzthiophene derived ER PROTACs ER-α Luciferase IC50 *ObsdSynthetic Ex. # Structure (nM) [M + H]⁺ Method 170

   5.6 830.2 Scheme 1B 171

   8.7 802.1 Scheme 1B 172

   15.7 828.1 Scheme 1B 173

   8 844.2 Scheme 1B 174

   0.54 764.2 Scheme 2B 175

   66.7 859.1 Scheme 3B 176

   28.7 858.1 Scheme 1B 177

   2.3 840.1 Scheme 4B 178

   2.4 854.2 Scheme 5B 179

   1 814.2 Scheme 2B 180

   0.22 776.2 Scheme 6B 181

   2.2 776.2 Scheme 6B 182

   1.9 839.1 Scheme 7B 183

   2.5 866.4 Scheme 8B 184

   13.3 880.5 Scheme 9B 185

   4.5 852.4 Scheme 10B 186

>300 866.4 Scheme 11B 187

  5.1 825.5 Scheme 12B 188

  8.7 839.5 Scheme 12B, 13B 189

  3 852.4 Scheme 14B 190

  11.6 865.4 Scheme 15B 191

  1.8 866.4 Scheme 14B 192

  2.9 840.5 Scheme 16B 193

  9.8 858.5 Scheme 16B, 17B 194

  3.9 852.5 Scheme 16B 195

  2.9 870.5 Scheme 16B, 17B 196

  8.6 851.5 Scheme 15B 197

  2.8 853.4 Scheme 18B 198

  10.2 852.5 Scheme 19B 199

  0.82 839.5 Scheme 18B 200

  8.4 854.5 Scheme 16B 201

  8.4 872.5 Scheme 17B 202

  14.8 868.5 Scheme 9B 203

  4.7 876.5 Scheme 20B 204

  16.4 872.3 Scheme 21B 205

  3.5 888.4 Scheme 20B 206

  13.3 888.5 Scheme 20B 207

  11.4 771.5 Scheme 22B 208

  8.4 801.4 Scheme 17B, 22B 209

  2.8 807.4 Scheme 23B 210

  2.3 769.1 Scheme 22B 211

  31.6 795.4 Scheme 24B 212

  15 809.4 Scheme 25B 213

  11.2 809.4 Scheme 26B 214

  10.4 807.4 Scheme 27B 215

  5.3 781.4 Scheme 24B 216

  2.7 793.4 Scheme 27B 217

  7.5 787.5 Scheme 22B 218

  58.2 823.4 Scheme 20B, 28B 219

  19.1 805.4 Scheme 21B, 28B 220

  1.5 721.4 Scheme 22B 221

  2.4 739.4 Scheme 22B 222

  8.9 801.4 Scheme 29B 223

  41.1 809.4 Scheme 30B 224

   7.7 793.1 Scheme 31B 225

   4.8 797.4 Scheme 32B 226

   1.2 760.5 Scheme 33B 227

  7 774.5 Scheme 33B 228

  24.9 836.4 Scheme 33B 229

  1 774.5 Scheme 33B 230

  1.1 761.5 Scheme 33B, 34B 231

  7.1 822.4 Scheme 35B 232

  1.6 761.5 Scheme 36B 233

  2.1 795.4 Scheme 25B, 38B 234

  0.65 772.5 Scheme 6B, 33B 235

  6.9 823.4 Scheme 34B, 35B 236

  4.9 823.4 Scheme 36B 237

  4.9 786.5 Scheme 6B, 33B 238

  10.9 840.4 Scheme 35B, 37B 239

  13.5 841.4 Scheme 34B, 37B 240

  1.2 795.4 Scheme 38B 241

  6.7 793.4 Scheme 38B, 39B 242

  18.7 859.4 Scheme 40B 243

  0.18 759.5 Scheme 41B 244

  0.18 758.5 Scheme 41B 245

  0.53 772.5 Scheme 41B *Observed [M + Na]⁺ from LC/MS

TABLE 4 Data for VHL centric benzthiophene derived ER PROTACs D_(max)Ex. # IUPAC ¹H-NMR DC₅₀* (%)** 111 (2S,4R)-1-((S)-2-tert-butyl-14-(4- δ1.03 (s, 9H), 1.49 (d, J = 6.8 Hz, 3H), A A (2-(4-fluorophenyl)-6-1.92-1.99 (m, 1H), 2.18-2.23 (m, 1H), hydroxybenzo[b]thiophen-3- 2.48,2.49 (two singles, 3H), 3.70-3.75 yloxy)phenoxy)-4-oxo-6,9,12- (m, 9H),3.81-3.86 (m, 3H), 4.03-4.09 (m, trioxa-3-azatetradecane)-4- 4H), 4.43(br, 1H), 4.55-4.59 (m, 1H), hydroxy-N-((S)-1-(4-(4- 4.68 (br, 1H),4.97-5.02 (m, 1H), methylthiazol-5- 6.78-6.81 (m, 1H), 6.85-6.87 (m,4H), yl)phenyl)ethyl)pyrrolidine-2- 7.07-7.12 (m, 2H), 7.18-7.20 (m,2H), carboxamide 7.38-7.45 (m, 4H), 7.12-7.76 (m, 2H), 8.88, 8.89 (twosingles, 1H). (CD₃OD, 400 MHz) 117 (2S,4R)-1-((S)-2-(2-(2-(1-(2-(4- δ1.02, 1.04 (two singles, 9H), 2.06-2.11 B B (2-(4-fluorophenyl)-6- (m,1H), 2.24-2.27 (m, 1H), 2.45, 2.47 hydroxybenzo[b]thiophen-3- (twosingles, 3H), 3.54-3.87 (m, 8H), yloxy)phenoxy)ethyl)azetidin-3-4.06-4.58 (m, 13H), 4.76-4.80 (m, 1H), yloxy)ethoxy)acetamido)-3,3-6.76-6.89 (m, 5H), 7.06-7.10 (m, 2H), dimethylbutanoyl)-4-hydroxy-N-7.15-7.21 (m, 2H), 7.38-7.44 (m, 4H), (4-(4-methylthiazol-5- 7.67-7.75(m, 2H), 8.41 (br, 1H), 8.86, yl)benzyl)pyrrolidine-2- 8.89 (twosingles, 1H). (CD₃OD, 400 MHz) carboxamide 118[2S,4R)-1-((S)-2-(2-(2-(4-(2-(4- δ 1.02, 1.05 (two singles, 9H),2.07-2.12 A A ((2-(4-fluorophenyl)-6- (m, 1H), 2.21-2.27 (m, 1H), 2.47,2.48 hydroxybenzo[b]thiophen-3- (two singles, 3H), 2.94-3.22 (m, 12H),yl)oxy)phenoxy)ethyl)piperazin- 3.80-3.88 (m, 4H), 4.07-4.18 (m, 4H),1-yl)ethoxy)acetamido)-3,3- 4.34-4.38 (m, 1H), 4.50-4.55 (m, 3H),dimethylbutanoyl)-4-hydroxy-N- 4.70 (br, 1H), 6.78-6.86 (m, 5H),(4-(4-methylthiazol-5- 7.07-7.12 (m, 2H), 7.17-7.18 (m, 1H), 7.21yl)benzyl)pyrrolidine-2- (d, J = 2.0 Hz, 1H), 7.39-7.45 (m, 4H),carboxamide] 7.72-7.76 (m, 2H), 8.87, 8.88 (two singles, 1H). (CD₃OD,400 MHz) 119 (2S,4R)-1-((S)-2-tert-butyl-14-(4- δ 1.03 (s, 9H),1.47-1.57 (m, 3H), B A (2-(4-chlorophenyl)-6- 1.93-1.99 (m, 1H),2.18-2.23 (m, 1H), 2.47, hydroxybenzo[b]thiophen-3- 2.48 (two singles,3H), 3.67-3.76 (m, 9H), yloxy)phenoxy)-4-oxo-6,9,12- 3.81-3.86 (m, 3H),4.03-4.09 (m, 4H), trioxa-3-azatetradecane)-4- 4.38 (br, 1H), 4.55-4.59(m, 1H), 4.68(s, hydroxy-N-((S)-1-(4-(4- 1H), 4.96-5.01 (m, 1H),6.78-6.81 (m, methylthiazol-5- 5H), 7.18-7.21 (m, 2H), 7.33-7.45(m, 6H),yl)phenyl)ethyl)pyrrolidine-2- 7.70-7.72 (m, 2H), 8.87, 8.89 (twosingles, carboxamide 1H). (CD₃OD, 400 MHz) 121(2S,4R)-1-[(2S)-2-[2-(4-[1-[2-(4- δ 9.01 (s, 1H) 7.74-7.69 (m, 5H), B A[[2-(4-fluorophenyl)-6-hydroxy- 7.49-7.43 (m, 4H), 7.36-7.34 (m, 2H),1-benzothiophen-3- 7.34-7.10 (m, 4H), 6.82-6.79 (m, 3H),yl]oxy]phenoxy)ethyl]-1H- 6.78-6.76 (m, 1H), 6.60-6.59 (m, J =pyrazol-3-yl[phenyl)acetamido]- 2.4 Hz, 1H), 4.64-4.50 (m, 6H),4.38-4.30 3,3-dimethylbutanoyl]-4- (m, 3H), 3.89-3.81 (m, 2H), 3.65-3.63(m, hydroxy-N-[[4-(4-methyl-1,3- 2H), 2.45 (s, 3H), 2.25-2.20 (m, 1H),thiazol-5- 2.08-2.02 (m, 1H), 1.00 (s, 9H). (CD₃OD,yl)phenyl]methyl]pyrrolidine-2- 400 MHz) carboxamide 126(2S,4R)-1-((S)-14-(4-(2-(4- δ 1.03 (s, 9H), 1.47-1.57 (m, 3H), A Abromophenyl)-6- 1.93-1.99 (m, 1H), 2.17-2.23 (m, 1H), 2.47,hydroxybenzo[b]thiophen-3- 2.48 (two singles, 3H), 3.66-3.76 (m, 9H),yloxy)phenoxy)-2-tert-butyl-4- 3.80-3.87 (m, 3H), 4.03-4.08 (m, 4H),oxo-6,9,12-trioxa-3- 4.44 (br, 1H), 4.55-4.59 (m, 1H), 4.68 (d,azatetradecane)-4-hydroxy-N- J = 9.2 Hz, 1H), 4.96-5.03 (m, 1H), 6.79((S)-1-(4-(4-methylthiazol-5- (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.85, 6.86yl)phenyl)ethyl)pyrrolidine-2- (two singles, 4H), 7.17-7.20 (m, 2H),carboxamide 7.37-7.44 (m, 4H), 7.48-7.50 (m, 2H), 7.62-7.66 (m, 3H),8.57 (d, J = 9.2 Hz, 1H), 8.87, 8.88 (two singles, 1H). (CD₃OD, 400 MHz)127 (2S,4R)-1-((S)-14-(4-(2-(4- δ 1.03 (s, 9H), 1.47-1.56 (m, 3H), A Abromophenyl)-6- 1.92-1.98 (m, 1H), 2.17-2.22 (m, 1H), 2.39,hydroxybenzo[b]thiophen-3- 2.41 (two singles, 3H), 3.67-3.76 (m, 9H),yloxy)phenoxy)-2-tert-butyl-4- 3.81-3.86 (m, 3H), 4.03-4.09 (m, 4H),oxo-6,9,12-trioxa-3- 4.44 (br, 1H), 4.55-4.59 (m, 1H), 4.67-4.70azatetradecane)-4-hydroxy-N- (m, 1H), 4.96-5.01 (m, 1H), 6.79 (dd,((S)-1-(4-(4-methyloxazol-5- J = 8.4 Hz, 2.0 Hz, 1H), 6.85-6.87 (m,yl)phenyl)ethyl)pyrrolidine-2- 4H), 7.18-7.21 (m, 2H), 7.39-7.42 (m,carboxamide 2H), 7.48-7.50 (m, 2H), 7.60-7.66(m, 4H), 8.14, 8.16 (twosingles, 1H). (CD₃OD, 400 MHz) 128 (2S,4R)-1-[(2S)-2-[1-(4-[[2-(4- δ8.94 (s, 1H), 7.76 (m, 2H), 7.43 (m, A A fluorophenyl)-6-hydroxy-1- 4H),7.20 (m, 2H), 7.10 (m, 2H), 6.95 (m, benzothiophen-3-yl]oxy]phenyl)-5H), 5.01 (m, 1H), 4.75 (m, 1H), 4.55 (m, 4-methyl-1,7,10-trioxa-4- 1H),4.30 (m, 3H), 4.05 (m, 4H), 3.70 (m, azadodecan-12-amido]-3,3- 10H),3.04 (s, 3H), 2.49 (s, 3H), 2.29 (m, dimethylbutanoyl]-4-hydroxy-N- 1H),1.95 (m, 1H), 1.45 (m, 3H), 1.02 (s, [(1S)-1-[4-(4-methyl-1,3-thiazol-9H). (CD₃OD, 400 MHz) 5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide 129(2S,4R)-N-[(1S)-1-(4- δ 7.76 (m, 2H), 7.30 (m, 6H), 7.13 (m, B Achlorophenyl)ethyl]-1-[(2S)-2-[1- 2H), 6.92 (m, 4H), 6.81 (m, 1H), 4.91(m, (4-[[2-(4-fluorophenyl)-6- 1H), 4.72 (m, 1H), 4.57 (m, 1H), 4.35 (m,hydroxy-1-benzothiophen-3- 3H), 3.92 (m, 5H), 4.75 (m, 5H), 3.65 (m,yl]oxy]phenyl)-4-methyl-1,7,10- 3H), 3.45 (m, 1H), 3.05 (s, 3H), 2.22(m, trioxa-4-azadodecan-12-amido]- 1H), 1.88 (m, 1H), 1.44 (m, 3H), 1.01(s, 3,3-dimethylbutanoyl]-4- 9H). (CD₃OD, 400 MHz) hydroxypyrrolidine-2-carboxamide 130 (2S,4R)-1-[(2S)-2-[3-(3-[1-[2-(4- δ 9.30 (s, 1H),7.69-7.68 (m, 3H), 7.67-7.64 B A [[2-(4-fluorophenyl)-6-hydroxy- (d, J =8.8 Hz 1H) 7.56-7.54 (d, J = 7.6 1-benzothiophen-3- Hz, 1H), 7.42-7.41(m, 4H), 7.29-7.27 yl]oxy]phenoxy)ethyl]-1H- (d, J = 7.6 Hz, 1H),7.15-7.04 (m, 5H), pyrazol-3- 6.80 (s, 4H), 6.77-6.76 (m, 1H), 6.56 (s,yl]phenyl)propanamido]-3,3- 1H), 4.56-4.49 (m, 6H), 4.35-4.29 (m,dimethylbutanoyl]-4-hydroxy-N- 3H), 3.90-3.85 (m, 1H), 3.75-3.70 (m,[[4-(4-methyl-1,3-thiazol-5- 1H), 3.00-2.95 (m, 2H), 2.70-2.59 (m,yl)phenyl]methyl]pyrrolidine-2- 2H), 2.49 (s, 3H), 2.21-2.11 (m, 1H),carboxamide 2.06-2.03 (m, 1H), 0.88 (s, 9H). (CD₃OD, 400 MHz) 133(2S,4R)-1-[(2S)-2-[2-(4-[[6-(4- δ 8.89 (s, 1H), 8.39 (s, 1H), 8.00 (m,2H), B A [[2-(4-fluorophenyl)-6-hydroxy- 7.72-7.78 (m, 4H), 7.36-7.45(m, 4H), 1-benzothiophen-3- 7.24-7.27 (m, 2H), 7.09-7.14 (m, 4H),yl]oxy]phenyl)pyridin-3- 6.83-6.86 (m, 1H), 4.71-7.42 (m, 1H),yl]oxy]butoxy)acetamido]-3,3- 4.50-4.59 (m, 3H), 4.26-4.38 (m, 3H),dimethylbutanoyl]-4-hydroxy-N- 3.97-4.04 (m, 2H), 3.88 (m, 1H), 3.83 (m,[[4-(4-methyl-1,3-thiazol-5- 1H), 3.65-3.68 (m, 2H), 2.44 (s, 3H),yl)phenyl]methyl]pyrrolidine-2- 2.28-2.21 (m, 1H), 2.00-2.09 (m, 3H),carboxamide 1.86-1.90 (m, 2H), 1.04 (s, 9H). (CD₃OD, 400 MHz) 134(2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4- δ 8.81 (s, 1H), 7.76-7.71 (m, 3H),7.57 (d, B A [[2-(4-fluorophenyl)-6-hydroxy- J = 8.8 Hz, 2H), 7.42-7.31(m, 4H), 1-benzothiophen-3- 7.25-7.20 (m, 2H), 7.12-7.08 (m, 2H), 7.02yl]oxy]phenyl)-2-oxo-1,2- (d, J = 8.8 Hz, 2H), 6.84-6.81 (m, 1H), 6.67dihydropyridin-1- (m, 1H), 6.62-6.59 (m, 1H), 4.71 (s, 1H),yl]ethoxy]ethoxy)acetamido]-3,3- 4.61-4.48 (m, 3H), 4.31-4.16 (m, 3H),dimethylbutanoyl]-4-hydroxy-N- 4.07-3.95 (m, 2H), 3.90-3.77 (m, 4H),[[4-(4-methyl-1,3-thiazol-5- 3.72-3.58 (m, 4H), 2.42 (s, 3H), 2.28-2.20yl)phenyl]methyl]pyrrolidine-2- (m, 1H), 2.12-2.06 (m, 1H), 1.03 (s,9H). carboxamide (CD₃OD, 300 MHz) 135 (2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-δ 9.88 (s, 1H), 8.96 (s, 1H), 8.59 (m, 1H), A A[[2-(4-fluorophenyl)-6-hydroxy- 7.68-7.72 (m, 2H), 7.39-7.42 (m, 5H),1-benzothiophen-3- 7.24-7.31 (m, 3H), 7.12-7.14 (m, 3H),yl]oxy]phenyl)piperidin-1- 6.81-6.85 (m, 3H), 5.15-5.16 (m, 1H),yl]ethoxy]ethoxy)acetamido]-3,3- 4.55-4.57 (m, 1H), 4.35-4.44 (m, 3H),dimethylbutanoyl]-4-hydroxy-N- 4.19-4.27 (m, 1H), 3.97 (s, 2H),3.65-3.69 [[4-(4-methyl-1,3-thiazol-5- (m, 1H), 3.59-3.61 (m, 3H),3.52-3.56 (m, yl)phenyl]methyl]pyrrolidine-2- 4H), 2.92 (d, J = 10.8 Hz,2H), 2.49 (m, carboxamide 2H), 2.42 (s, 3H), 2.30-2.38 (m, 1H),1.86-2.08 (m, 4H), 1.50-1.64 (m, 4H), 0.94 (s, 9H). (DMSO-d₆, 400 MHz)138 (2S,4R)-1-((S)-2-tert-butyl-14-(4- δ 1.02, 1.03 (two singles, 9H),1.47-1.56 A A (6-hydroxy-2- (m, 3H), 1.93-1.99 (m, 1H), 2.16-2.22 (m,phenylbenzo[b]thiophen-3- 1H), 2.39, 2.40 (two singles, 3H),yloxy)phenoxy)-4-oxo-6,9,12- 3.69-3.76 (m, 9H), 3.80-3.86 (m, 3H),trioxa-3-azatetradecane)-4- 4.02-4.08 (m, 4H), 4.43 (br, 1H), 4.55-4.59hydroxy-N-((S)-1-(4-(4- (m, 1H), 4.67-4.69 (m, 1H), 4.96-5.01methyloxazol-5- (m, 1H), 6.79 (dd, J = 8.4 Hz, 2.0 Hz, 1H),yl)phenyl)ethyl)pyrrolidine-2- 6.85, 6.86 (two singles, 4H), 7.18-7.26carboxamide (m, 3H), 7.31-7.35 (m, 2H), 7.40-7.42 (m, 2H), 7.59-7.65 (m,3H), 7.71-7.73 (m, 2H), 8.12, 8.14 (two singles, 1H). (CD₃OD, 400 MHz)139 (2S,4R)-1-[(2S)-2-[2-[3-(2-[[2-(4- δ 8.91 (s, 1H), 7.71-7.70 (m,2H), A A [[2-(4-fluorophenyl)-6-hydroxy- 7.45-7.41 (m, 4H), 7.30-7.28(m, 1H), 1-benzothiophen-3- 7.26-7.16 (m, 2H), 7.09-7.05 (m, 2H),yl]oxy]phenoxy)ethyl](methyl)ami- 7.00-6.96 (m, 7H), 6.78-6.76 (m, 1H),no]ethyl)phenoxy]acetamido]- 4.79-4.76 (m, 1H), 4.64-4.56 (m, 4H),3,3-dimethylbutanoyl]-4- 4.36-429 (m, 3H), 3.92-3.70 (m, 3H),hydroxy-N-[[4-(4-methyl-1,3- 3.62-3.53 (m, 4H), 3.19-3.01 (m, 5H),thiazol-5- 2.45 (s, 3H), 2.26-2.20 (m, 1H), 2.09-2.00yl)phenyl]methyl]pyrrolidine-2- (m, 1H), 10.98 (s, 9H). (CD₃OD, 400 MHz)carboxamide 140 (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4- δ 8.81 (s, 1H),7.63-7.61 (d, J = 8.4 Hz, B A [[2-(4-bromophenyl)-6-hydroxy- 2H),7.48-7.46 (d, J = 8.4 Hz, 2H), 1-benzothiophen-3- 7.44-7.41 (m, 2H),7.39-7.36 (m, 2H), yl]oxy]phenoxy)ethyl]piperazin- 7.19-7.18 (m, 2H),6.83-6.76 (m, 5H), 1-yl]ethoxy)acetamido]-3,3- 4.68 (s, 1H), 4.53-4.50(m, 3H), 4.31-4.30 dimethylbutanoyl]-4-hydroxy-N- (m, 1H), 4.04-3.98 (m,4H), 3.97-3.94 [[4-(4-methyl-1,3-thiazol-5- (m, 2H), 3.69-3.67 (m, 2H),2.74-2.65 yl)phenyl]methyl]pyrrolidine-2- (m, 12H), 2.67 (s, 3H),2.36-2.22 (m, 1H), carboxamide 2.12-2.01 (m, 1H), 1.00 (m, 9H). (CD₃OD,400 MHz) 141 (2S,4R)-1-[(2S)-2-[2-(4-[1-[2-(4- δ 8.91 (s, 1H), 7.85-7.71(m, 5H), B A [[2-(4-fluorophenyl)-6-hydroxy- 7.51-7.39 (m, 4H),7.34-7.31 (m, 2H), 1-benzothiophen-3- 7.25-7.05 (m, 4H), 6.94-6.78 (m,5H), 6.65 yl]oxy]phenoxy)ethyl]-1H- (s, 1H), 5.28-5.25 (m, 1H), 4.70-50(m, 4H), pyrazol-3-yl]phenyl)acetamido]- 4.50-4.40 (m, 1H), 4.40-4.38(m, 2H), 3,3-dimethylbutanoyl]-4- 3.92-3.82 (m, 1H), 3.80-3.70 (m, 1H),hydroxy-N-[(1S)-1-[4-(4-methyl- 3.70-3.55 (m, 2H), 2.55 (s, 3H),2.23-2.21 1,3-thiazol-5-yl)phenyl]ethyl]pyrro- (m, 1H), 1.95-1.91 (m,1H), 1.47-1.43 (m, lidine-2-carboxamide 3H), 1.00 (s, 9H). (CD₃OD, 300MHz) 142 (2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4- δ 8.87 (s, 1H), 7.72 (m, 3H),7.40 (m, A A [[2-(4-fluorophenyl)-6-hydroxy- 4H), 7.15 (m, 6H), 6.92 (m,1H), 6.79 (m, 1-benzothiophen-3- 1H), 4.97 (m, 1H), 4.72 (m, 1H), 4.55(m, yl]oxy]phenyl)piperidin-1- 1H), 4.30 (m, 1H), 4.09 (m, 2H), 3.89 (m,yl]ethoxy]ethoxy)acetamido]-3,3- 2H), 3.74 (m, 7H), 3.45 (m, 3H), 3.18(m, dimethylbutanoyl]-4-hydroxy-N- 2H), 2.89 (m, 1H), 2.45 (s, 3H), 2.22(m, [(1S)-1-[4-(4-methyl-1,3-thiazol- 1H), 2.11 (m, 2H), 1.95 (m, 3H),1.45 (m, 5-yl)phenyl]ethyl]pyrrolidine-2- 3H), 1.05 (s, 9H). (CD₃OD, 400MHz) carboxamide 147 (2S,4R)-N-[(1S)-1-(4- δ 7.77 (m, 4H), 7.45 (m, 2H),7.20 (m, B A cyanophenyl)ethyl]-1-[(2S)-2-[2- 4H), 7.09 (m, 2H), 6.92(m, 2H), 6.79 (m, (2-[2-[4-(4-[[2-(4-fluorophenyl)- 1H), 4.93 (m, 1H),4.72 (m, 1H), 4.55 (m, 6-hydroxy-1-benzothiophen-3- 1H), 4.30 (m, 1H),4.09 (m, 2H), 3.89 (m, yl]oxy]phenyl)piperidin-1- 2H), 3.74 (m, 7H),3.45 (m, 3H), 3.18 (m, yl]ethoxy]ethoxy)acetamido]-3,3- 2H), 2.89 (m,1H), 2.22 (m, 1H), 2.12 (m, dimethylbutanoyl]-4- 2H), 1.90 (m, 3H), 1.45(m, 3H), 1.02 hydroxypyrrolidine-2- (s, 9H). (CD₃OD, 400 MHz)carboxamide 149 (2S,4R)-N-[(1S)-1-(4- δ 7.77-7.70 (m, 7H), 7.70-7.47 (m,2H), B A cyanophenyl)ethyl]-1-[(2S)-2-[2- 7.36-7.34 (m, 2H), 7.20-7.06(m, 4H), (4-[1-[2-(4-[[2-(4-fluorophenyl)- 6.83-6.77 (m, 5H) 6.60 (s 1H)5.00-4.98 6-hydroxy-1-benzothiophen-3- (m, 1H), 4.62-5.52 (m, 4H),4.50-4.31 (m, yl]oxy]phenoxy)ethyl]-1H- 3H), 3.89-3.86 (m, 1H),3.75-3.32 (m, pyrazol-3-yl]phenyl)acetamido]- 3H), 2.18-2.15 (m, 1H),1.95-1.90 (m, 3,3-dimethylbutanoyl]-4- 1H), 1.49-1.47 (m, 3H), 1.00 (s,9H). hydroxypyrrolidine-2- (CD₃OD, 300 MHz) carboxamide 150(2S,4R)-N-[(1S)-1-(4- δ 7.74-7.71 (m, 5H), 7.38-7.30 (m, 5H), C Achlorophenyl)ethyl]-1-[(2S)-2-[2- 7.27-7.06 (m, 5H), 6.83-6.80 (m, 5H),(4-[1-[2-(4-[[2-(4-fluorophenyl)- 6.60 (s, 1H), 4.95-4.93 (m, 1H), 4.876-hydroxy-1-benzothiophen-3- (m, 1H), 4.63 (s, 1H), 4.57-4.54 (m, 3H),yl]oxy]phenoxy)ethyl]-1H- 4.50-4.42 (m, 1H), 4.35-4.31 (m, 2H),pyrazol-3-yl]phenyl)acetamido]- 3.89-3.85 (m, 1H), 3.76-3.75 (m, 1H),3,3-dimethylbutanoyl]-4- 3.65-3.56 (m, 2H), 2.21-2.11 (m, 1H),hydroxypyrrolidine-2- 1.94-1.91 (m, 1H), 1.47-1.43 (m, 3H), carboxamide0.99 (s, 9H). (CD₃OD, 300 MHz) 151 (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4- δ8.818 (s, 1H) 7.69-7.66 (m, 2H), A A [[2-(4-chlorophenyl)-6-hydroxy-7.50-7.30 (m, 6H), 7.18-7.14 (m, 2H), 1-benzothiophen-3- 6.83-6.75 (m,5H), 4.79 (s, 1H), 4.67-4.48 yl]oxy]phenoxy)ethyl]piperazin- (m, 4H),4.31-4.26 (m, 1H), 4.08-3.98 1-yl]ethoxy)acetamido]-3,3- (m, 4H),3.93-3.80 (m, 2H), 3.79-3.75 dimethylbutanoyl]-4-hydroxy-N- (m, 2H),2.90-2.61 (m, 11H), 2.43 (s, 3H), [[4-(4-methyl-1,3-thiazol-5- 2.19-2.11(m, 1H), 2.10-2.06 (m, 1H), yl)phenyl]methyl]pyrrolidine-2- 1.01 (s,9H). (CD₃OD, 300 MHz) carboxamide 153 (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-δ 8.90-8.80 (s, 1H), 7.64-7.61 (m, 2H), B A[[2-(4-bromophenyl)-6-hydroxy- 7.49-7.46 (m 2H), 7.43-7.36 (m, 4H),1-benzothiophen-3- 7.19-7.17 (m, 2H), 6.86-6.83 (m, 4H),yl]oxy]phenoxy)ethyl]piperazin- 6.79-6.76 (m, 1H), 4.99-4.97 (m, 1H),1-yl]ethoxy)acetamido]-3,3- 4.67 (s, 1H), 4.60-4.52 (m, 1H), 4.40 (m,dimethylbutanoyl]-4-hydroxy-N- 1H), 4.12-4.05 (m, 4H), 3.90-3.75 (m,[(1S)-1-[4-(4-methyl-1,3-thiazol- 4H), 3.10-2.85 (m, 11H), 2.46-2.45 (s,5-yl)phenyl]ethyl]pyrrolidine-2- 3H), 2.25-2.15 (m, 1H), 2.00-1.95 (m,carboxamide 1H), 1.75-1.65 (m, 1H), 1.50 (s, 3H), 1.39-1.26 (m, 3H),1.01 (s, 9H). (CD₃OD, 400 MHz) 158 (2S,4R)-1-[(2S)-2-[2-(4-[2-[2-(4- δ8.862 (s, 1H), 8.323 (s, 1H), 7.64-7.60 C A[[2-(4-bromophenyl)-6-hydroxy- (m, 2H), 7.49-7.37 (m, 5H), 7.18-7.15 (m,1-benzothiophen-3- 2H), 6.83-6.75 (m, 5H), 4.63-4.31 (m,yl]oxy]phenoxy)ethoxy]ethyl]pi- 5H), 4.08-4.05 (m, 2H), 3.85-3.78 (m,perazin-1-yl)acetamido]-3,3- 5H), 3.18-3.07 (m, 7H), 2.71-2.62 (m,dimethylbutanoyl]-4-hydroxy-N- 3H), 2.45-2.40 (m, 3H), 2.29-2.03 (m,[[4-(4-methyl-1,3-thiazol-5- 2H), 1.28-1.27 (m, 1H), 1.01-0.99 (m,yl)phenyl]methyl]pyrrolidine-2- 9H). (CD₃OD, 300 MHz) carboxamide 160(2S,4R)-1-[(2S)-2-[2-(4-[3-[2-(4- δ 8.87 (d, J = 8.3 Hz, 1H), 7.69-7.59(m, B A [[2-(4-bromophenyl)-6-hydroxy- 2H), 7.54-7.37 (m, 6H), 7.24-7.14(m, 1-benzothiophen-3- 2H), 6.90-6.74 (m, 5H), 4.65-4.46 (m,yl]oxy]phenoxy)ethoxy]azetidin- 4H), 4.36 (d, J = 15.3 Hz, 1H), 4.25 (s,1-yl]piperidin-1-yl)acetamido]- 1H), 4.03 (d, J = 4.7 Hz, 2H), 3.95-3.703,3-dimethylbutanoyl]-4- (m, 6H), 3.65-3.54 (m, 1H), 3.06 (s, 3H),hydroxy-N-[[4-(4-methyl-1,3- 2.89 (m, 2H), 2.47 (m, 3H), 2.23 (t,thiazol-5- J = 11.1 Hz, 2H), 2.20-2.08 (m, 1H), 1.83yl)phenyl]methyl]pyrrolidine-2- (m, 2H), 1.30 (m, 4H), 1.02 (d, J = 8.9Hz, carboxamide 9H), 0.10 (m, 2H). (CD₃OD, 300 MHz) 164(2S,4R)-1-[(2S)-2-[3-[2-[4-[2-[4- δ 8.89 (s, 1H), 7.64 (d, J = 8.8 Hz,2H), B B [2-(4-bromophenyl)-6-hydroxy- 7.51-7.48 (m, 6H), 7.22-7.19 (m,2H), benzothiophen-3- 6.92-6.79 (m, 5H), 6.05 (s, 1H),yl]oxyphenoxy]ethyl]piperazin-1- 4.60-4.42 (m, 6H), 3.90-3.68 (m, 5H),yl]ethoxy]isoxazol-5-yl]-3- 3.20-2.74 (m, 12H), 2.49 (s, 3H), 2.48-2.45methyl-butanoyl]-4-hydroxy-N- (m, 1H), 2.38-2.35 (m, 1H), 2.10-2.08[[4-(4-methylthiazol-5- (m, 1H), 1.05 (d, J = 7.2 Hz, 3H), 0.90 (d,yl)phenyl]methyl]pyrrolidine-2- J = 7.2 Hz, 3H). (CD₃OD, 400 MHz)carboxamide *and **ER-alpha degradation measured in MCF7 cells westernblot assay following 3 days of incubation *DC50: A < 1 nM; B 1 to 10 nM;C 10-100 nM **Dmax: A > 75%; B 50% to 75%; C < 50%

TABLE 5 Data for cereblon centric benzthiophene derived ER PROTACs DC₅₀D_(max) Ex. # IUPAC Name H-NMR (nM)* (%)**  33 3-[5-[2-[2-[4-[2-(4- δ10.95 (s, 1H), 9.92 (s, 1H), 7.65-7.60 (m, 5H), B B bromophenyl)-6- 7.31(d, J = 2.0 Hz, 1H), 7.17-7.14 (m, 2H), 7.07 hydroxy-benzothiophen-3-(dd, J = 8.8, 2.0 Hz, 1H), 6.88 (s, 4H), 6.83 (dd, J =yl]oxyphenoxy]ethoxy]eth- 8.8, 2.0 Hz, 1H), 5.07 (dd, J = 13.2, 5.2 Hz,oxy]-1-oxo-isoindolin- 1H), 4.41-4.36 (m, 1H), 4.29-4.24 (m, 1H),2-yl]piperidine-2,6-dione 4.21-4.19 (m, 2H), 4.05-4.03 (m, 2H), 3.81 (m,4H), 2.95-2.86 (m, 1H), 2.56-2.53 (m, 1H), 2.37-2.36 (m, 1H), 1.97-1.94(m, 1H). (400 MHz, DMSO-d6)  52 3-(6-(4-(5-(4-(2-(4- δ 1.39-1.44 (2H,m), 1.46-1.52 (2H, m), 1.66-1.71 C B bromophenyl)-6- (2H, m), 1.93-1.99(1H, m), 2.28-2.33 hydroxybenzo[b]thiophen- (4H, m), 2.54-2.56 (2H, m),2.61-2.67 (1H, m), 3-yloxy)phenoxy)pentyl)pi- 2.87-2.93 (1H, m),3.22-3.32 (5H, m), 3.88 (2H, t, perazin-1-yl)-1- J = 6.4 Hz), 4.18-4.34(2H, m), 5.04 (1H, dd, J = oxoisoindolin-2- 4.8, 13.2 Hz), 6.82 (1H, dd,J = 2.0, 8.4 Hz), 6.86 yl)piperidine-2,6-dione (4H, s), 7.03-7.06 (2H,m), 7.14 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.51 (1H, d, J =8.8 Hz), 7.62 (4H, s), 9.92 (1H, s), 10.94 (1H, s). (400 MHz, DMSO-d6) 57 1-(2-(4-(2-(4- δ 1.57-1.69 (4H, m), 1.97-2.02 (3H, m), 2.12-2.16 B Bbromophenyl)-6- (1H, m), 2.36-2.04 (1H, m), 2.57-2.64 (3H,hydroxybenzo[b]thiophen- m), 2.88-2.94 (3H, m), 3.97 (2H, t, J = 5.6Hz), 3-yloxy)phenoxy)ethyl)- 4.27-4.45 (4H, m), 5.10 (1H, dd, J = 13.2,5.2 N-((2-(2,6- Hz), 6.81-6.84 (1H, m), 6.87 (4H, s), 7.15 (1H, d,dioxopiperidin-3-yl)-1- J = 8.8 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.36 (1H,d, oxoisoindolin-5- J = 7.6 Hz), 7.43 (1H, s), 7.62 (4H, s), 7.67 (1H,yl)methyl)piperidine-4- d, J = 8.0 Hz), 8.38 (1H, t, J = 6.0 Hz), 9.93(1H, carboxamide s), 10.97 (1H, s). (400 MHz, DMSO-d6)  615-(4-(5-(4-(2-(4- δ 1.40-1.54 (4H, m), 1.66-1.73 (2H, m), 1.99-2.02 C Bbromophenyl)-6- (1H, m), 2.31 (2H, t, J = 7.4 Hz), 2.47-2.51hydroxybenzo[b]thiophen- (5H, m), 2.53-2.60 (1H, m), 2.83-2.93 (1H, m),3-yloxy)phenoxy)pentyl)pi- 3.36-3.41 (4H, m), 3.88 (2H, t, J = 6.2 Hz),5.07 perazin-1-yl)-2(2,6- (1H, dd, J = 5.2, 12.8 Hz), 6.82 (1H, dd, J =2.0, dioxopiperidin-3- 8.4 Hz), 6.86 (4 H, s), 7.15 (1H, d, J = 8.8 Hz),yl)isoindoline-1,3-dione 7.24 (1H, dd, J = 2.0, 8.4 Hz), 7.32 (2H, dd, J= 1.6, 9.6 Hz), 7.62 (4H, s), 7.67 (1H, d, J = 8.8 Hz), 9.92 (1H, s),11.08 (1H, s). (400 MHz, DMSO-d6)  74 3-(5-(3-(4-(2-(4-(2-(4- δ1.40-1.50 (2H, m), 1.65-1.78 (2H, m), 1.90-2.03 B A bromophenyl)-6- (1H,m), 2.59-2.94 (12H, m), 3.07-3.12 (2H, hydroxybenzo[b]thiophen- m),3.30-3.33 (2H, m), 3.90-4.02 (2H, m), 4.09-4.28 3-yloxy)phenoxy)ethyl)-(2H, m), 4.99-5.03 (1H, m), 5.32 (1H, t, J = 1,4-diazepan-1- 4.6 Hz),6.41 (1H, t, J = 5.4 Hz), 6.62-6.66 (2H, yl)propylamino)-1- m),6.81-6.87 (5H, m), 7.15 (1H, d, J = 8.8 Hz), oxoisoindolin-2- 7.30 (1H,d, J = 2.0 Hz), 7.38 (1H, d, J = 8.4 Hz), yl)piperidine-2,6-dione7.60-7.464 (4H, m), 9.93 (1H, s), 10.92 (1H, s). (400 MHz, DMSO-d6)  893-[5-[3-[3-[2-[4-[2-(4- δ 10.93 (s, 1H), 9.93 (s, 1H), 7.64-7.59 (m,4H), B B bromophenyl)-6- 7.37 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.0 Hz,1H), hydroxy-benzothiophen- 7.14 (d, J = 8.8 Hz, 1H), 6.86 (s, 4H), 6.82(dd, 3-yl]oxyphenoxy]ethoxy]pro- J = 2.0, 8.4 Hz, 1H), 6.66-6.59 (m,2H), 6.35 (t, poxy]propylamino]-1- J = 5.2 Hz, 1H), 5.01 (dd, J = 5.2,13.2 Hz, 1H), oxo-isoindolin-2- 4.29-4.22 (m, 1H), 4.16-4.09 (m, 1H),4.01-3.95 yl]piperidine-2,6-dione (m, 2H), 3.68-3.61 (m, 2H), 3.48 (t, J= 6.4 Hz, 2H), 3.43-3.38 (m, 4H), 3.16-3.06 (m, 2H), 2.95-2.82 (m, 1H),2.52 (s, 1H), 2.34-2.23 (m, 1H), 1.96-1.88 (m, 1H), 1.81-1.68 (m, 4H).(400 MHz, DMSO-d6)  94 3-[5-[3-[3-[3-[4-[2-(4- δ 10.94 (s, 1H), 10.01(s, 1H), 7.68-7.57 (m, B B bromophenyl)-6- 4H), 7.38 (d, J = 8.4 Hz,1H), 7.31 (d, J = 2.0 Hz, hydroxy-benzothiophen-3- 1H), 7.15 (d, J = 8.8Hz, 1H), 6.91-6.79 (m, 5H), yl]oxyphenoxy]propoxy] 6.68-6.58 (m, 2H),6.35 (t, J = 5.6 Hz, 1H), 5.02 propoxy]propylamino]-1- (m, 1H),4.31-4.07 (m, 2H), 3.92 (t, J = 6.0 Hz, oxo-isoindolin-2- 2H), 3.47 (t,J = 6.0 Hz, 2H), 3.44-3.39 (m, 6H), yl]piperidine-2,6-dione 3.11 (m,2H), 2.97-2.81 (m, 1H), 2.59 (m, 2H), 2.37-2.29 (m, 1H), 1.91-1.86 (m,2H), 1.74 (m, 4H). (400 MHz, DMSO-d6)  95 3-[5-[3-[2-[2-[4-[2-(4- δ10.91 (s, 1H), 9.99 (s, 1H), 7.59 (s, 4H), 7.35 C bromophenyl)-6- (d, J= 8.4 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.12 hydroxy-benzothiophen- (d,J = 8.8 Hz, 1H), 6.85 (s, 4H), 6.80 (dd, J = 2.1, 3-yl]oxyphenoxy]eth-8.8 Hz, 1H), 6.64-6.58 (m, 2H), 6.33 (t, J = 5.2 Hz,oxy]ethoxy]propylamino]-1- 1H), 4.99 (dd, J = 5.2, 13.2 Hz, 1H),4.26-4.20 oxo-isoindolin-2- (m, 1H), 4.14-4.08 (m, 1H), 4.00-3.95 (m,yl]piperidine-2,6-dione 2H), 3.71-3.66 (m, 2H), 3.58-3.53 (m, 2H),3.50-3.44 (m, 4H), 2.92-2.81 (m, 1H), 1.93-1.86 (m, 1H), 1.79-1.71 (m,2H). (400 MHz, CDCl₃) 174 3-[5-[3-[4-[2-[4-[2-(4- δ 10.93 (s, 1H), 8.20(s, 1H), 7.72-7.68 (m, 2H), A A fluorophenyl)-6-hydroxy- 7.37 (d, J =8.4 Hz, 1H), 7.30-7.24 (m, 3H), 7.13 benzothiophen-3- (d, J = 8.8 Hz,1H), 6.86 (s, 4H), 6.82 (dd, J = 2.0, yl]oxyphenoxy]ethyl]pi- 8.8 Hz,1H), 6.65-6.13 (m, 2H), 6.40 (br s, 1H), perazin-1- 5.01 (dd, J = 5.2,13.2 Hz, 1H), 4.28-4.24 (m, yl]propylamino]-1-oxo- 1H), 4.15-4.11 (m,1H), 3.97 (t, J = 5.6 Hz, 4H), isoindolin-2- 3.09 (t, J = 6.0 Hz, 2H),2.94-2.84 (m, 2H), yl]piperidine-2,6-dione 2.67-2.63 (m, 3H), 2.52-2.50(m, 5H), 2.37-2.29 (m, 5H), 1.94-1.92 (m, 1H), 1.72-1.67 (m, 1H). (400MHz, DMSO-d6) 177 5-[3-[4-[2-[4-[2-(4- δ 11.07 (s, 1H), 8.29 (s, 2H),7.62 (s, 4H), 7.55 B A bromophenyl)-6- (d, J = 8.4 Hz, 1H), 7.31 (d, J =2.0 Hz, 1H), hydroxy-benzothiophen- 7.17-7.12 (m, 2H), 6.95 (d, J = 1.6Hz, 1H), 3-yl]oxyphenoxy]ethyl]pi- 6.88-6.81 (m, 6H), 5.03 (dd, J = 5.6,12.8 Hz, 1H), perazin-1- 3.98 (t, J = 5.6 Hz, 2H), 3.23-3.14 (m, 2H),yl]propylamino]-2-(2,6- 2.92-2.82 (m, 1H), 2.59 (d, J = 3.2 Hz, 4H),dioxo-3- 2.54-2.52 (m, 5H), 2.41-2.30 (m, 4H),piperidyl)isoindoline-1,3- 2.03-1.95 (m, 1H), 1.70 (t, J = 6.8 Hz, 2H),dione 1.74-1.66 (m, 1H). (400 MHz, DMSO-d6) 178 5-[3-[4-[2-[4-[2-(4- δ11.07 (s, 1H), 8.31 (s, 2H), 7.66-7.58 (m, 4H), B A bromophenyl)-6- 7.55(d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), hydroxy-benzothiophen-7.20-7.12 (m, 2H), 6.94 (d, J = 1.6 Hz, 1H), 3-yl]oxyphenoxy]ethyl]-6.88-6.80 (m, 6H), 5.02 (dd, J = 5.2, 12.8 Hz, 1H),1,4-diazepan-1-yl]propyl- 3.95 (t, J = 5.6 Hz, 2H), 3.22-3.14 (m, 2H),amino]-2-(2,6-dioxo-3- 2.93-2.77 (m, 4H), 2.75-2.69 (m, 4H), 2.65-2.57piperidyl)isoindo- (m, 5H), 2.52 (s, 2H), 1.99 (td, J = 4.4, 6.8 Hz,line-1,3-dione 1H), 1.73-1.63 (m, 4H). (400 MHz, DMSO-d6) 1793-[5-[3-[4-[2-[4-[6- δ 10.94 (s, 1H), 10.01 (s, 1H), 7.89 (d, J = 8.4Hz, B B hydroxy-2-[4- 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.38-7.34 (m, 2H),(trifluoromethyl) 7.17 (d, J = 8.4 Hz, 1H), 6.88 (m, 4H), 6.84 (dd,phenyl]benzothiophen-3- J = 2.0, 8.8 Hz, 1H), 6.65-6.61 (m, 2H), 6.41(t, yl]oxyphenoxy]ethyl]pi- J = 4.8 Hz, 1H), 5.01 (dd, J = 5.1, 13.4 Hz,1H), perazin-1- 4.28-4.24 (m, 1H), 4.15-4.11 (m, 1H), 3.98 (t,yl]propylamino]-1-oxo- J = 5.6 Hz, 2H), 3.33-3.32 (m, 2H), 3.11-3.08isoindolin-2- (m, 2H), 2.94-2.85 (m, 1H), 2.67-2.57 (m,yl]piperidine-2,6-dione 4H), 2.54-2.52 (m, 4H), 2.42-2.23 (m, 4H),1.94-1.91 (m, 1H), 1.75-1.61 (m, 2H). (400 MHz, DMSO-d6) 1803-[5-[3-[4-[2-[4-[6- δ 10.94 (s, 1H), 8.17 (s, 1H), 7.65-7.57 (m, 2H), AA hydroxy-2-(4- 7.38 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H),methoxyphenyl) 7.11 (d, J = 8.8 Hz, 1H), 7.02-6.95 (m, 2H),benzothiophen-3- 6.89-6.83 (m, 4H), 6.81 (dd, J = 2.1, 8.8 Hz,yl]oxyphenoxy]ethyl]pi- 1H), 6.69-6.59 (m, 2H), 6.54-6.32 (m, 1H),perazin-1- 5.02 (dd, J = 5.0, 13.2 Hz, 1H), 4.32-4.11 (m,yl]propylamino]-1-oxo- 2H), 4.04-3.92 (m, 3H), 3.75 (s, 3H), 3.10 (t,isoindolin-2- J = 6.0 Hz, 2H), 2.97-2.83 (m, 1H), 2.70-2.56yl]piperidine-2,6-dione (m, 4H), 2.47-2.24 (m, 9H), 1.97-1.91 (m, 1H),1.70 (t, J = 6.8 Hz, 2H). (400 MHz, DMSO-d6) 181 3-[5-[3-[4-[2-[4-[2-(4-δ 10.94 (s, 1H), 8.28 (s, 2H), 7.58-7.49 (m, 3H), B B hydroxyphenyl)-6-7.38 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H),methoxy-benzothiophen-3- 6.93 (dd, J = 2.3, 8.8 Hz, 1H), 6.89-6.83 (m,yl]oxyphenoxy]ethyl]pi- 4H), 6.80 (d, J = 8.8 Hz, 2H), 6.67-6.60 (m,perazin-1- 2H), 6.41 (s, 1H), 5.01 (dd, J = 5.0, 13.2 Hz, 1H),yl]propylamino]-1-oxo- 4.32-4.07 (m, 2H), 4.02-3.92 (m, 3H), 3.82 (s,3H), isoindolin-2- 3.10 (s, 2H), 2.95-2.83 (m, 1H), 2.71-2.53 (m, 4H),yl]piperidine-2,6-dione 2.45-2.24 (m, 9H), 1.97-1.90 (m, 1H), 1.75-1.60(m, 2H). (400 MHz, DMSO-d6) 182 (3S)-3-[5-[2-[4-[4-[4-[4-[2- δ11.57-11.19 (m, 1H), 11.18-10.87 (m, 2H), B A (4-bromophenyl)-6- 9.97(s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.64-7.62 hydroxy-benzothiophen- (m,4H), 7.54 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 3-yl]oxyphenoxy]butyl]-7.32 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H),1,4-diazepan-1-yl]ethyl]- 6.92-6.79 (m, 5H), 5.12 (dd, J = 4.8, 12.8 Hz,1-oxo-isoindolin-2- 1H), 4.48-4.40 (m, 1H), 4.36-4.27 (m, 1H),yl]piperidine-2,6-dione 3.92 (t, J = 5.6 Hz, 2H), 3.83-3.66 (m, 4H),3.64-3.49 (m, 2H), 3.49-3.40 (m, 3H), 3.18 (s, 4H), 2.98-2.84 (m, 1H),2.65-2.56 (m, 1H), 2.56-2.53 (m, 1H), 2.41-2.34 (m, 1H), 2.30-2.16 (m,2H), 2.04-1.93 (m, 1H), 1.83 (s, 2H), 1.76-1.67 (m, 2H). (400 MHz,DMSO-d6) 183 5-[4-[1-[2-[4-[2-(4- δ 11.69 (s, 1H), 11.10 (s, 1H), 10.79(s, 1H), C B bromophenyl)-6- 10.02 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H),7.62 (s, hydroxy-benzothiophen- 4H), 7.48 (s, 1H), 7.33 (s, 2H), 7.15(d, J = 8.8 3-yl]oxyphenoxy]ethyl]- Hz, 1H), 7.01-6.78 (m, 5H), 5.09 (d,J = 7.6 Hz, 4-piperidyl]piperazin-1- 1H), 4.43-4.07 (m, 4H), 3.79-3.44(m, 3H), yl]-2(2,6-dioxo-3- 3.33-3.30 (m, 7H), 3.20-2.99 (m, 4H), 2.89(s, piperidyl)isoindoline-1,3- 2H), 2.67 (s, 1H), 2.35 (d, J = 16.4 Hz,2H), dione 2.25-1.92 (m, 2H). (400 MHz, DMSO-d6) 1845-[4-[1-[2-[4-[2-(4- δ 11.10 (s, 1H), 11.06-10.80 (m, 1H), 10.7-10.3 C Abromophenyl)-6- (m, 1H), 9.99 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H),hydroxy-benzothiophen- 7.62 (s, 4H), 7.49 (s, 1H), 7.39-7.30 (m,3-yl]oxyphenoxy]ethyl]- 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.99-6.88 (m,4H), 4-piperidylmethyl]piperazin- 6.84 (dd, J = 2.0, 8.8 Hz, 1H), 5.09(dd, J = 5.2, 1-yl]-2-(2,6-dioxo-3- 12.8 Hz, 1H), 4.33 (s, 2H), 4.19 (d,J = 14.0 Hz, piperidyl)isoindoline-1,3- 2H), 3.68-3.49 (m, 6H), 3.44 (s,2H), 3.27-2.97 dione (m, 6H), 2.95-2.81 (m, 1H), 2.63-2.52 (m, 2H),2.22-1.94 (m, 4H), 1.70-1.47 (m, 2H). (400 MHz, DMSO-d6) 1855-[4-[[1-[2-[4-[2-(4- δ 11.08 (s, 1H), 8.21 (s, 1H), 7.67 (d, J = 8.4Hz, B B bromophenyl)-6- 1H), 7.62 (s, 4H), 7.35-7.29 (m, 2H), 7.24 (dd,hydroxy-benzothiophen- J = 2.4, 8.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H),3-yl]oxyphenoxy]ethyl]azeti- 6.90-6.79 (m, 5H), 5.07 (dd, J = 5.6, 12.8Hz, 1H), din-3-yl]methyl]pi- 3.83 (t, J = 5.2 Hz, 2H), 3.44-3.38perazin-1- (m, 7H), 2.94-2.82 (m, 3H), 2.75-2.69 yl]-2(2,6-dioxo-3- (m,2H), 2.65-2.55 (m, 4H), piperidyl)isoindoline-1,3- 2.46-2.41 (m, 4H),2.07-1.96 (m, 1H). dione (400 MHz, DMSO-d6) 190 5-(1′-(2-(4-((2-(4-6 δ11.32-11.15 (m, 1H), 11.14 (s, 1H), 10.70 B B bromophenyl)-6- (br s,1H), 9.99 (br s, 1H), 7.97-7.91 (m, 1H), hydroxybenzo[b]thiophen-3-7.81-7.72 (m, 2H), 7.70-7.61 (m, 4H), 7.36-7.33 yl)oxy)phenoxy)ethyl)-(m, 1H), 7.20-7.13 (m, 1H), 7.02-6.91 (m, [1,4′-bipiperidin]-4-yl)-2-4H), 6.88-6.82 (m, 1H), 5.22-5.10 (m, 1H), (2,6-dioxopiperidin-3-4.42-4.26 (m, 2H), 3.81-3.42 (m, 9H), 3.21-3.04 yl)isoindoline-1,3-dione(m, 4H), 2.99-2.84 (m, 1H), 2.70-2.56 (m, Hydrochloride 2H), 2.43-1.99(m, 8H). (400 MHz, DMSO-d6) 191 5-(3-((4-(2-(4-((2-(4- δ 11.09 (s, 3H),10.13-9.79 (m, 1H), 7.72-7.66 B B bromophenyl)-6- (m, 1H), 7.63 (s, 3H),7.48 (d, J = 8.1 Hz, 1H), hydroxybenzo[b]thiophen-3- 7.33 (d, J = 2.1Hz, 1H), 7.18-7.14 (m, 1H), yl)oxy)phenoxy)ethyl)- 7.13-7.09 (m, 1H),6.98-6.92 (m, 3H), 6.87-6.82 1,4-diazepan-1- (m, 1H), 6.81-6.77 (m, 1H),6.68-6.63 (m, yl)methyl)azetidin-1-yl)- 1H), 5.08 (br d, J = 12.8 Hz,1H), 4.41-4.26 (m, 2-(2,6-dioxopiperidin-3- 2H), 4.26-4.14 (m, 2H), 3.86(br s, 3H), 3.67-3.48 yl)isoindoline-1,3-dione (m, 6H), 3.33-3.09 (m,1H), 3.33-3.09 (m, 2H), 2.97-2.81 (m, 1H), 2.63-2.53 (m, 5H), 2.29 (s,3H), 2.06-1.95 (m, 1H). (400 MHz, DMSO-d6) 192 3-[5-[4-[1-[2-[4-[6- δ10.95 (s, 1H), 10.02 (s, 1H), 8.15 (s, 1H), 7.90 C A hydroxy-2-[4- (d, J= 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.51 (trifluoromethyl)phen- (d,J = 8.8 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.18 yl]benzothiophen-3- (d,J = 8.8 Hz, 1H), 7.10-7.01 (m, 2H), 6.95-6.81 yl]oxyphenoxy]ethyl]-4-(m, 5H), 5.04 (dd, J = 5.2, 13.2 Hz, 1H), 4.39-4.13piperidyl]piperazin-1-yl]- (m, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.26 (s,1-oxo-isoindolin-2- 5H), 3.05-2.84 (m, 3H), 2.72 (s, 2H), 2.62 (s,yl]piperidine-2,6-dione 4H), 2.43-2.34 (m, 1H), 2.24 (s, 1H), 2.17-2.03(m, 2H), 2.00-1.90 (m, 1H), 1.77 (d, J = 11.6 Hz, 2H), 1.52-1.37 (m,2H). (400 MHz, DMSO-d6) 193 3-[4-fluoro-5-[4-[1-[2-[4- δ 10.99 (s, 1H),8.19 (s, 1H), 7.90 (d, J = 8.4 Hz, B A [6-hydroxy-2-[4- 2H), 7.78 (d, J= 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, (trifluoromethyl)phen- 1H), 7.34 (d,J = 2.0 Hz, 1H), 7.19-7.12 (m, yl]benzothiophen-3- 2H), 6.89 (s, 4H),6.85 (dd, J = 2.0, 8.8 Hz, 1H), yl]oxyphenoxy]ethyl]-4- 5.07 (dd, J =5.1, 13.4 Hz, 1H), 5.50-4.46 (m, piperidyl]piperazin-1-yl]- 1H),4.33-4.28 (m, 1H), 3.98 (t, J = 5.6 Hz, 2H), 1-oxo-isoindolin-2-3.18-3.11 (m, 4H), 2.97-2.87 (m, 3H), 2.67-2.60 yl]piperidine-2,6-dione(m, 6H), 2.44-2.39 (m, 2H), 2.23-2.18 (m, 1H), 2.04-1.95 (m, 3H),1.76-1.73 (m, 2H), 1.46-1.38 (m, 2H). (400 MHz, DMSO-d6) 1943-[5-[4-[1-[2-[4-[2-(4- δ 10.95 (s, 1H), 8.18 (s, 2H), 7.62 (s, 4H),7.51 B A bromophenyl)-6- (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H),7.15 hydroxybenzothiophen-3- (d, J = 8.8 Hz, 1H), 7.11-7.00 (m, 2H),6.92-6.79 yl]oxyphenoxy]ethyl]-4- (m, 5H), 5.04 (dd, J = 5.2, 13.6 Hz,1H), 4.37-4.14 piperidyl]piperazin-1-yl]- (m, 2H), 3.97 (t, J = 5.6 Hz,2H), 3.26 (s, 1-oxo-isoindolin-2- 5H), 3.00-2.85 (m, 3H), 2.65-2.57 (m,6H), yl]piperidine-2,6-dione 2.43-2.34 (m, 1H), 2.20 (s, 1H), 2.08-1.91(m, 3H), 1.75 (d, J = 10.8 Hz, 2H), 1.41 (q, J = 10.8 Hz, 2H). (400 MHz,DMSO-d6) 199 3-[5-[4-[4-[2-[4-[2-(4- δ 10.98 (s, 1H), 8.20 (s, 1H),7.72-7.57 (m, 5H), B B bromophenyl)-6- 7.42 (s, 1H), 7.37-7.30 (m, 2H),7.15 (d, J = 8.8 hydroxybenzothiophen-3- Hz, 1H), 6.87 (s, 4H), 6.83(dd, J = 2.1, 8.8 Hz, yl]oxyphenoxy]ethyl]- 1H), 5.10 (dd, J = 5.0, 13.2Hz, 1H), 4.46-4.38 1,4-diazepan-1-yl]butyl]- (m, 1H), 4.33-4.24 (m, 1H),3.96 (m, 2H), 2.97-2.80 1-oxo-isoindolin-2- (m, 4H), 2.75-2.67 (m, 9H),2.58 (s, 2H), yl]piperidine-2,6-dione 2.45-2.33 (m, 2H), 2.03-1.96 (m,1H), 1.78-1.69 (m, 2H), 1.64-1.55 (m, 2H), 1.51-1.41 (m, 2H). (400 MHz,DMSO) 201 3-[4-fluoro-5-[4-[[1-[2- δ 10.99 (s, 1H), 10.05-10.00 (m, 1H),8.14 (s, 2H), C A [4-[6-hydroxy-2- 7.90 (d, J = 8.0 Hz, 2H), 7.78 (d, J= 8.4 Hz, [4-(trifluoromethyl)phen- 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.34(d, J = 2.0 Hz, yl]benzothiophen-3- 1H), 7.19-7.13 (m, 2H), 6.91 (s,4H), 6.85 (dd, yl]oxyphenoxy]ethyl]-4- J = 2.0, 8.8 Hz, 1H), 6.58-6.54(m, 1H), 5.07 piperidyl]methyl]piperazin-1- (dd, J = 5.2, 13.4 Hz, 1H),5.50-4.46 (m, 1H), yl]-1-oxo-isoindolin- 4.33-4.29 (m, 1H), 4.07-4.02(m, 2H), 3.21-3.13 2-yl]piperidine-2,6-dione (m, 8H), 2.98-2.81 (m, 4H),2.63-2.52 (m, 2H), 2.46-2.34 (m, 3H), 2.25-2.16 (m, 2H), 1.98-1.94 (m,1H), 1.76-1.57 (m, 3H), 1.23-1.14 (m, 2H). (400 MHz, DMSO-d6) 2053-[5-[4-[1-[2-[4-[2-(4- δ 11.00 (s, 1H), 8.19 (s, 1H), 7.64-7.60 (m,4H), C A bromophenyl)-6- 7.39 (d, J = 10.0 Hz, 1H), 7.30 (d, J = 2.0 Hz,1H), hydroxybenzothiophen-3- 7.15 (d, J = 8.4 Hz, 1H), 6.87-6.81 (m,5H), 5.08 yl]oxyphenoxy]ethyl]-4- (dd, J = 5.2, 13.4 Hz, 1H), 4.49-4.45(m, 1H), pipendyl]piperazin-1-yl]- 4.33-4.28 (m, 1H), 3.98 (t, J = 6.0Hz, 2H), 4,6-difluoro-1-oxo- 3.20-3.18 (m, 4H), 2.98-2.87 (m, 4H),2.65-2.55 isoindolin-2- (m, 6H), 2.43-2.39 (m, 1H), 2.25-2.19 (m, 1H),yl]piperidine-2,6-dione 2.05-1.96 (m, 3H), 1.75-1.71 (m, 2H), 1.48-1.39(m, 2H). (400 MHz, DMSO-d6) 213 5-[3-[4-[4-[2-(4- δ 11.07 (s, 1H), 8.32(s, 1H), 7.67-7.59 (m, 5H), C bromophenyl)-6- 7.30 (d, J = 2.0 Hz, 1H),7.16 (d, J = 8.8 Hz, 1H), hydroxybenzothiophen-3- 6.91-6.81 (m, 5H),6.78 (d, J = 2.0 Hz, 1H), 6.65 yl]oxyphenoxy]-1- (dd, J = 2.0, 8.4 Hz,1H), 5.05 (dd, J = 5.6, 13.0 piperidyl]azetidin-1-yl]- Hz, 1H),4.34-4.24 (m, 1H), 4.10 (t, J = 7.6 Hz, 2H), 2-(2,6-dioxo-3- 3.83 (dd, J= 5.2, 8.8 Hz, 2H), 2.94-2.80 (m, 1H), piperidyl)isoindoline-1,3-2.65-2.54 (m, 2H), 2.56-2.52 (br s, 3H), 2.23-2.14 dione (m, 2H),2.06-1.94 (m, 1H), 1.96-1.94 (m, 2H), 1.64-1.58 (m, 2H). (400 MHz,DMSO-d6) 214 5-[4-[[3-[4-[2-(4- δ 9.61 (s, 1H), 7.11-7.03 (m, 3H),6.78-6.69 B B bromophenyl)-6- (m, 3H), 6.62 (d, 1H), 6.53-6.43 (m, 3H),6.22 hydroxybenzothiophen-3- (d, 2H), 4.96-4.73 (m, 1H), 4.13 (d, 1H),3.41 yl]oxyphenyl]azetidin-1- (d, 2H), 3.37-3.23 (m, 1H), 3.04-2.86 (m,2H), yl]methyl]-1-piperidyl]- 2.73-2.62 (m, 2H), 2.33-2.21 (m, 1H),2.17-2.01 2-(2,6-dioxo-3- (m, 1H), 1.95-1.86 (m, 2H), 1.77-1.62 (m,piperidyl)isoindoline-1,3- 3H). (400 MHz, CDCl₃) dione 2153-[5-[4-[4-[4-[2-(4- δ 10.94 (s, 1H), 9.98 (s, 1H), 8.22 (s, 1H), 7.61 BB bromophenyl)-6- (s, 4H), 7.51 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 2.0hydroxybenzothiophen-3- Hz, 1H), 7.14 (dd, J = 5.6, 8.8 Hz, 3H),7.06-7.01 yl]oxyphenyl]butyl]piper- (m, 2H), 6.88-6.80 (m, 3H), 5.04(dd, J = 4.8, azin-1-yl]-1-oxo- 13.2 Hz, 1H), 4.36-4.28 (m, 1H),4.23-4.15 isoindolin-2- (m, 1H), 3.24 (s, 3H), 2.95-2.85 (m, 1H),2.63-2.54 yl]piperidine-2,6-dione (m, 2H), 2.47-2.36 (m, 6H), 2.33-2.25(m, 3H), 1.96 (d, J = 5.0 Hz, 1H), 1.59-1.40 (m, 4H). (400 MHz, DMSO-d6)216 3-[5-[4-[[3-[4-[2-(4- δ 10.97-10.91 (m, 1H), 8.33 (s, 2H), 7.62 (s,4H), B B bromophenyl)-6- 7.47 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 2.1 Hz,hydroxy-benzothiophen- 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8Hz, 3-yl]oxyphenyl]azetidin- 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.86-6.81(m, 1H), 1-yl]methyl]-1- 6.62-6.58 (m, 2H), 5.03 (dd, J = 5.2, 13.2 Hz,piperidyl]-1-oxo- 1H), 4.32-4.15 (m, 2H), 3.61-3.45 (m, 2H),isoindolin-2- 3.03-2.87 (m, 5H), 2.64-2.53 (m, 5H), 2.30-2.26yl]piperidine-2,6-dione (m, 1H), 2.18-1.89 (m, 3H), 1.69-1.57 (m, 1H),1.49-1.40 (m, 2H), 1.26-1.22 (m, 1H). (400 MHz, DMSO-d6) 2173-[5-[4-[3-[4-[6-hydroxy- δ 10.95 (s, 1H), 10.10-9.78 (m, 1H), 8.24-8.12B B 2-[4-(trifluoro- (m, 1H), 7.84-7.77 (m, 2H), 7.55-7.49 (m,methoxy)phen- 1H), 7.47-7.41 (m, 2H), 7.35-7.31 (m, 1H),yl]benzothiophen-3- 7.19-7.13 (m, 1H), 7.10-7.03 (m, 2H), 6.89 (s,yl]oxyphenoxy]propyl]pi- 4H), 6.86-6.80 (m, 1H), 5.10-5.00 (m, 1H),perazin-1-yl]-1-oxo- 4.38-4.16 (m, 2H), 4.00-3.91 (m, 2H), 3.28-3.26isoindolin-2- (m, 4H), 2.97-2.83 (m, 1H), 2.53 (s, 4H),yl]piperidine-2,6-dione 2.47-2.39 (m, 4H), 2.00-1.85 (m, 3H). (400 MHz,DMSO-d6) 220 3-[5-[4-[3-[4-[2-(4- δ 10.95 (s, 1H), 9.91 (s, 1H),7.74-7.68 (m, 2H), B B fluorophenyl)-6- 7.59 (d, J = 8.4 Hz, 1H),7.33-7.23 (m, 3H), hydroxybenzothiophen-3- 7.19-7.11 (m, 3H), 6.89 (s,4H), 6.83 (dd, J = 2.1, yl]oxyphenoxy]propyl]pi- 8.7 Hz, 1H), 5.06 (dd,J = 5.0, 13.3 Hz, 1H), perazin-1-yl]-1-oxo- 4.42-4.18 (m, 2H), 4.08-3.96(m, 4H), 3.62 (d, isoindolin-2- J = 10.4 Hz, 2H), 3.29 (s, 2H),3.25-3.12 (m, yl]piperidine-2,6-dione 4H), 2.98-2.83 (m, 1H), 2.59 (d, J= 17.4 Hz, 1H), 2.38 (dd, J = 4.5, 13.1 Hz, 1H), 2.17 (s, 2H), 2.00-1.93(m, 1H). (400 MHz, DMSO-d6) 221 3-[5-[4-[3-[4-[2-(3,4- δ 10.95 (s, 1H),9.51 (s, 1H), 8.14 (s, 1H), 7.70-7.64 B B difluorophenyl)-6- (m, 1H),7.55-7.47 (m, 3H), 7.31 (d, J = 2.0 hydroxy-benzothiophen- Hz, 1H), 7.16(d, J = 8.8 Hz, 1H), 7.06-7.04 (m, 3-yl]oxyphenoxy]propyl]pi- 2H), 6.88(s, 4H), 6.84 (dd, J = 2.4, 8.8 Hz, 1H), perazin-1-yl]-1-oxo- 5.04 (dd,J = 5.2, 13.2 Hz, 1H), 4.34-4.30 (m, isoindolin-2- 1H), 4.22-4.17 (m,1H), 3.95 (d, J = 6.4 Hz, 2H), yl]piperidine-2,6-dione 3.28-3.30 (m,8H), 2.94-2.85 (m, 1H), 2.60-2.56 (m, 1H), 2.46-2.34 (m, 2H), 2.38-2.33(m, 1H), 1.99-1.84 (m, 3H). (400 MHz, DMSO-d6) 223trans-5-[4-[3-[4-[2-(4- δ 11.09 (s, 1H), 9.93 (s, 1H), 8.25 (s, 1H),7.67 C A bromophenyl)-6- (d, J = 8.4 Hz, 1H), 7.65-7.58 (m, 4H), 7.34(d, hydroxy-benzothiophen- J = 1.6 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H),7.28-7.23 3-yl]oxyphenoxy]cyclobu- (m, 1H), 7.15 (d, J = 8.8 Hz, 1H),6.89-6.81 tyl]piperazin-1-yl]-2-(2,6- (m, 3H), 6.79-6.73 (m, 2H), 5.07(dd, J = 5.2, dioxo-3-piperidyl)iso- 12.8 Hz, 1H), 4.72-4.62 (m, 1H),3.45-3.43 (m, 4H), indoline-1,3-dione 2.94-2.83 (m, 2H), 2.62-2.53 (m,2H), 2.44-2.39 (m, 4H), 2.39-2.34 (m, 2H), 2.16-2.09 (m, 2H), 2.05-1.97(m, 1H). (400 MHz, DMSO-d6) 224 3-[5-[4-[3-[4-[2-(4- δ 10.94 (s, 1H),9.97-9.87 (m, 1H), 7.62 (s, 4H), B B bromophenyl)-6- 7.51-7.49 (d, J =0.8 Hz, 1H), 7.30-7.29 (d, J = 4 hydroxy-benzothiophen- Hz, 1H),7.16-7.14 (d, J = 8 Hz, 1H), 7.06 (s, 2H), 3-yl]oxyphenoxy]cyclobu-6.92-6.75 (m, 5H), 5.10-4.98 (m, 1H), tyl]piperazin-1-yl]-1-oxo-4.43-4.28 (m, 2H), 4.24-4.14 (m, 1H), 3.28 (s, 4H), isoindolin-2-2.96-2.83 (m, 1H), 2.65-2.58 (m, 2H), 2.41 yl]piperidine-2,6-dione (s,5H), 2.36-2.10 (m, 2H), 2.18-2.06 (m, 1H), 2.01-1.91 (m, 1H), 1.89-1.78(m, 2H). (400 MHz, DMSO-d6) 225 5-[4-[2-[[4-[2-(4- δ 11.09 (s, 1H), 9.95(s, 1H), 7.68 (d, J = 8.4 Hz, C bromophenyl)-6- 1H), 7.62 (s, 4H), 7.33(d, J = 2.0 Hz, 2H), 7.28 hydroxy-benzothiophen- (d, J = 8.8 Hz, 2H),7.24 (d, J = 8.4 Hz, 1H), 7.16 3-yl]oxyphenyl] (d, J = 8.8 Hz, 1H), 6.93(d, J = 8.8 Hz, 2H), 6.84 methoxy]ethyl]piperazin- (dd, J = 2.0, 8.8 Hz,1H), 5.11-5.04 (m, 1H), 4.41 1-yl]-2-(2,6-dioxo-3- (s, 2H), 3.56 (t, J =5.6 Hz, 2H), 3.40 (s, 4H), 3.31 piperidyl)isoindoline-1,3- (s, 2H), 2.90(d, J = 13.6 Hz, 1H), 2.61 (s, 2H), dione 2.56-2.54 (m, 4H), 2.06-1.99(m, 1H). (400 MHz, DMSO-d6) 226 3-[5-[4-[[1-[4-[2-(4- δ 10.95 (s, 1H),8.19 (s, 1H), 7.71 (dd, J = 5.4, 8.8 B A fluorophenyl)-6-hydroxy- Hz,2H), 7.52 (d, J = 8.8 Hz, 1H), 7.33-7.24 (m, benzothiophen-3- 3H), 7.14(d, J = 8.7 Hz, 1H), 7.08-7.03 (m, 2H), yl]oxyphenyl]-4- 6.89-6.79 (m,5H), 5.04 (dd, J = 5.1, 13.4 Hz, piperidyl]methyl]piperazin- 1H),4.36-4.29 (m, 1H), 4.23-4.17 (m, 1H), 1-yl]-1-oxo-isoindolin- 3.49-3.47(m, 4H), 3.33-3.30 (m, 6H), 2.95-2.85 2-yl]piperidine-2,6-dione (m, 1H),2.52 (d, J = 1.9 Hz, 3H), 2.35-2.32 (m, 1H), 2.21 (d, J = 7.2 Hz, 2H),2.00-1.92 (m, 1H), 1.79 (d, J = 10.9 Hz, 2H), 1.84-1.75 (m, 1H), 1.65(s, 1H), 1.27-1.14 (m, 2H). (400 MHz, DMSO-d6) 227 2-(2,6-dioxo-3- δ11.08 (s, 1H), 8.21 (s, 1H), 7.76-7.61 (m, 3H), B Apiperidyl)-5-[4-[[1-[4-[2- 7.33-7.20 (m, 5H), 7.13 (d, J = 8.7 Hz, 1H),(4-fluorophenyl)-6- 6.89-6.74 (m, 5H), 5.06 (dd, J = 5.3, 12.9 Hz, 1H),hydroxy-benzothiophen- 3.50 (d, J = 12.4 Hz, 8H), 2.93-2.81 (m, 1H),3-yl]oxyphenyl]-4- 2.69-2.52 (m, 6H), 2.20 (d, J = 7.2 Hz, 2H),piperidyl]methyl]piperazin-1- 2.04-1.97 (m, 1H), 1.83-1.59 (m, 3H),1.25-1.14 yl]isoindoline-1,3- (m, 2H). (400 MHz, DMSO-d6) dione 2285-[4-[[1-[4-[2-(4- δ 11.08 (s, 1H), 9.91 (s, 1H), 7.69-7.60 (m, B Abromophenyl)-6- 5H), 7.34-7.24 (m, 3H), 7.15 (d, J = 8.4 Hz, 1H),hydroxy-benzothiophen- 6.88-6.79 (m, 5H), 5.07 (dd, J = 4.4, 12.4 Hz,3-yl]oxyphenyl]-4- 1H), 3.53-3.37 (m, 6H), 3.31-3.17 (m, 2H),piperidyl]methyl]piperazin- 2.91-2.83 (m, 1H), 2.60-2.56 (m, 4H),2.45-2.35 1-yl]-2-(2,6-dioxo-3- (m, 2H), 2.21 (d, J = 6.8 Hz, 2H),2.02-1.99 piperidyl)isoindoline-1,3- (m, 1H), 1.81-1.77 (m, 2H),1.66-1.62 (m, dione 1H), 1.24-1.16 (m, 2H). (400 MHz, DMSO-d6) 2293-[5-[4-[2-[1-[4-[2-(4- δ 10.94 (s, 1H), 8.22 (s, 1H), 7.71 (dd, J =5.4, 8.8 B A fluorophenyl)-6-hydroxy- Hz, 2H), 7.51 (d, J = 8.9 Hz, 1H),7.30-7.23 (m, benzothiophen-3- 3H), 7.14 (d, J = 8.7 Hz, 1H), 7.08-7.02(m, 2H), yl]oxyphenyl]-4- 6.90-6.78 (m, 5H), 5.04 (dd, J = 5.1, 13.3 Hz,piperidyl]ethyl]piperazin- 1H), 4.36-4.17 (m, 2H), 3.50 (s, 8H), 3.27(s, 1-yl]-1-oxo-isoindolin-2- 3H), 2.94-2.84 (m, 1H), 2.63-2.54 (m, 2H),yl]piperidine-2,6-dione 2.35 (dd, J = 7.0, 14.4 Hz, 3H), 1.98-1.92 (m,1H), 1.75 (d, J = 11.5 Hz, 2H), 1.47-1.20 (m, 5H). (400 MHz, DMSO-d6)230 3-[2-[4-[[1-[4-[2-(4- δ 10.93 (s, 1H), 9.87 (s, 1H), 7.77-7.66 (m,3H), B A fluorophenyl)-6-hydroxy- 7.28-7.22 (m, 3H), 7.12 (d, J = 8.7Hz, 1H), benzothiophen-3- 6.89-6.77 (m, 6H), 5.04 (dd, J = 5.1, 13.4 Hz,1H), yl]oxyphenyl]-4- 4.25 (d, J = 17.3 Hz, 1H), 4.07 (d, J = 17.4 Hz,piperidyl]methyl]piperazin- 1H), 3.62 (s, 3H), 3.54-3.44 (m, 2H),2.94-2.82 (m, 1-yl]-5-oxo-7H- 1H), 2.53 (s, 3H), 2.41 (s, 6H), 2.17 (d,J = 6.9 Hz, pyrrolo[3,4-b]pyridin-6- 2H), 1.99-1.90 (m, 1H), 1.77 (d, J= 12.8 Hz, yl]piperidine-2,6-dione 2H), 1.62 (s, 1H), 1.23-1.13 (m, 2H).(400 MHz, DMSO-d6) 231 3-[5-[4-[[1-[4-[2-(4- δ 10.96 (s, 1H), 8.20 (s,1H), 7.63 (d, J = 1.6 Hz, B B bromophenyl)-6- 4H), 7.53 (d, J = 8.8 Hz,1H), 7.31 (d, J = 2.0 Hz, hydroxy-benzothiophen- 1H), 7.16 (d, J = 8.8Hz, 1H), 7.09-7.04 (m, 2H), 3-yl]oxyphenyl]-4- 6.91-6.79 (m, 5H), 5.05(dd, J = 5.2, 13.2 Hz, piperidyl]methyl]piperazin- 1H), 4.36-4.30 (m,1H), 4.24-4.17 (m, 1H), 1-yl]-1-oxo-isoindolin- 3.53 (d, J = 10.8 Hz,1H), 3.29 (br s, 7H), 2-yl]piperidine-2,6-dione 2.98-2.83 (m, 2H),2.63-2.54 (m, 4H), 2.40-2.35 (m, 1H), 2.22 (d, J = 6.8 Hz, 2H),2.01-1.92 (m, 1H), 1.80 (d, J = 11.2 Hz, 2H), 1.65 (br s, 1H), 1.27-1.15(m, 2H). (400 MHz, DMSO-d6) 232 3-[5-[4-[[1-[5-[2-(4- δ 10.94 (s, 1H),8.14 (s, 1H), 7.89 (d, J = 3.2 Hz, A A fluorophenyl)-6-hydroxy- 1H),7.73-7.67 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), benzothiophen-3-yl]oxy-7.32-7.19 (m, 4H), 7.11 (dd, J = 2.8, 9.2 Hz, 1H), 2-pyridyl]-4-7.08-7.01 (m, 2H), 6.84 (dd, J = 2.4, 8.8 Hz, 1H),piperidyl]methyl]piperazin- 6.74 (d, J = 9.6 Hz, 1H), 5.04 (dd, J = 5.2,13.2 Hz, 1-yl]-1-oxo-isoindolin- 1H), 4.37-4.28 (m, 1H), 4.23-4.15 (m,1H), 2-yl]piperidine-2,6-dione 4.14-4.06 (m, 2H), 3.29-3.21 (m, 7H),2.96-2.84 (m, 1H), 2.76-2.68 (m, 2H), 2.62-2.53 (m, 2H), 2.42-2.29 (m,1H), 2.22-2.15 (m, 2H), 2.01-1.90 (m, 1H), 1.80-1.68 (m, 3H), 1.16-1.00(m, 2H). (400 MHz, DMSO-d) 234 3-[5-[4-[[1-[4-[6- δ 10.94 (s, 1H), 9.78(s, 1H), 7.61 (d, J = 8.9 Hz, A B hydroxy-2-(4- 2H), 7.51 (d, J = 8.7Hz, 1H), 7.26 (d, J = 2.0 Hz, methoxyphenyl)benzothi- 1H), 7.13-6.97 (m,5H), 6.89-6.78 (m, 5H), ophen-3-yl]-oxyphenyl]- 5.04 (dd, J = 5.0, 13.2Hz, 1H), 4.35-4.16 (m, 4-piperidyl]methyl]piperazin- 2H), 3.75 (s, 3H),3.51 (d, J = 11.3 Hz, 2H), 3.29 1-yl]-1-oxo-isoindolin- (d, J = 9.5 Hz,5H), 2.96-2.83 (m, 1H), 2.66-2.52 2-yl]piperidine-2,6-dione (m, 7H),2.21 (d, J = 6.1 Hz, 2H), 1.98-1.92 (m, 1H), 1.79 (d, J = 11.9 Hz, 2H),1.64 (s, 1H), 1.21 (d, J = 16.3 Hz, 2H). (400 MHz, DMSO-d6) 2353-[2-[4-[[1-[4-[2-[4- δ 10.95 (s, 1H), 8.22 (s, 1H), 7.76 (d, J = 8.8Hz, B A bromophenyl)-6- 1H), 7.62 (d, J = 1.9 Hz, 4H), 7.29 (d, J = 2.0Hz, hydroxy-benzothiophen- 1H), 7.15 (d, J = 8.7 Hz, 1H), 6.92-6.80 (m,6H), 3-yl]oxyphenyl]-4- 5.06 (dd, J = 5.1, 13.1 Hz, 1H), 4.30-4.23 (m,piperidyl]methyl]piperazin- 1H), 4.09 (d, J = 17.4 Hz, 1H), 3.64 (s,4H), 1-yl]-5-oxo-7H- 2.94-2.82 (m, 1H), 2.57 (d, J = 14.2 Hz, 2H),pyrrolo[3,4-b]pyridin-6- 2.48-2.36 (m, 8H), 2.19 (d, J = 7.0 Hz, 2H),yl]piperidine-2,6-dione 2.01-1.91 (m, 1H), 1.83-1.76 (m, 2H), 1.64 (s,1H), 1.24-1.16 (m, 2H). (400 MHz, DMSO-d6) 236 3-[5-[4-[[1-[5-[2-(4- δ10.93 (s, 1H), 8.18 (s, 1H), 7.89 (d, J = 3.3 Hz, B A bromophenyl)-6-1H), 7.62 (s, 4H), 7.51 (d, J = 8.7 Hz, 1H), 7.30 hydroxy-benzothiophen-(d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.113-yl]oxy-2-pyridyl]-4- (dd, J = 3.1, 9.2 Hz, 1H), 7.08-7.02 (m, 2H),6.85 piperidyl]methyl]piperazin- (dd, J = 2.1, 8.7 Hz, 1H), 6.74 (d, J =9.4 Hz, 1H), 1-yl]-1-oxo-isoindolin- 5.04 (dd, J = 5.0, 13.4 Hz, 1H),4.35-4.16 (m, 2-yl]piperidine-2,6-dione 2H), 4.11 (d, J = 13.3 Hz, 2H),3.16 (s, 1H), 2.88 (d, J = 12.4 Hz, 1H), 2.76-2.56 (m, 6H), 2.44-2.29(m, 6H), 2.18 (d, J = 6.3 Hz, 2H), 2.00-1.90 (m, 1H), 1.76 (d, J = 10.7Hz, 3H), 1.11-1.04 (m, 2H). (400 MHz, DMSO-d6) 237 2-(2,6-dioxo-3- δ11.07 (s, 1H), 9.78 (s, 1H), 7.70-7.58 (m, C Apiperidyl)-5-[4-[[1-[4-[6- 3H), 7.35-7.21 (m, 3H), 7.13-7.08 (m, 1H),hydroxy-2-(4-methoxy- 7.13-7.08 (m, 1H), 6.97 (d, J = 8.9 Hz, 2H),phenyl)benzothiophen-3- 6.90-6.83 (m, 2H), 6.82-6.76 (m, 3H), 5.06 (dd,yl]oxyphenyl]-4- J = 5.4, 12.9 Hz, 1H), 3.75 (s, 3H), 3.53-3.40 (m,piperidyl]methyl]piperazin- 5H), 2.95-2.81 (m, 1H), 2.67-2.53 (m, 6H),1-yl]isoindoline-1,3- 2.32 (d, J = 1.8 Hz, 1H), 2.20 (d, J = 7.0 Hz,2H), dione 2.10-1.96 (m, 2H), 1.78 (d, J = 11.2 Hz, 2H), 1.63 (s, 1H),1.26-1.13 (m, 2H). (400 MHz, DMSO-d6) 238 3-[5-[4-[[1-[4-[2-(4- δ 10.95(s, 1H), 9.95 (br s, 1H), 8.18 (s, 1H), C A bromophenyl)-6- 7.64-7.60(m, 4H), 7.52 (d, J = 8.8 Hz, 1H), 7.33 hydroxy-benzothiophen- (d, J =2.0 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3-yl]oxy-2-fluoro- 7.09-7.03 (m,2H), 6.96 (t, J = 9.6 Hz, 1H), phenyl]-4- 6.90-6.83 (m, 2H), 6.61 (dd, J= 2.4, piperidyl]methyl]piperazin- 8.4 Hz, 1H), 5.05 (dd, J = 5.2,1-yl]-1-oxo-isoindolin- 13.2 Hz, 1H), 4.36-4.29 (m, 1H),2-yl]piperidine-2,6-dione 4.25-4.16 (m, 1H), 3.30-3.19 (m, 9H),2.96-2.85 (m, 1H), 2.64-2.53 (m, 4H), 2.42-2.35 (m, 1H), 2.23 (d, J =7.2 Hz, 2H), 2.00-1.93 (m, 1H), 1.79 (d, J = 12.8 Hz, 2H), 1.65 (br s,1H), 1.32-1.20 (m, 2H). (400 MHz, DMSO-d6) 239 3-[5-[4-[[1-[4-[2-(4- C Abromophenyl)-6- hydroxy-benzothiophen- 3-yl]oxyphenyl]-4-piperidyl]methyl]piperazin- 1-yl]-5-oxo-7H- pyrrolo[3,4-b]pyridin-6-yl]piperidine-2,6-dione 243 3-[2-[4-[[1-[4-[6- δ 8.33(s, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.53 (d, B B hydroxy-2-(4- J = 8.8 Hz, 2H), 7.16-7.13(m,1H), 6.95 (d, J = 8.8 hydroxyphenyl)benzothio- Hz, 2H), 6.90 (d, J = 6.8Hz, 1H), 6.83 (d, J = 9.2 phen-3-yl]oxyphenyl]-4- Hz, 2H), 6.77-6.73 (m,3H), 5.11 (dd, J = 4.8, 13.6 piperidyl]methyl]piperazin- Hz, 1H),4.35-4.24 (m, 2H), 3.8 (s, 4H), 3.52 (d, 1-yl]-5-oxo-7H- J = 12.0 Hz,2H), 2.93-2.84 (m, 1H), 2.78-2.75 (m, pyrrolo[3,4-b]pyridin-6- 5H),2.69-2.63(m, 2H), 2.52-2.47 (m, 2H), yl]piperidine-2,6-dione 2.44-2.41(m, 1H), 2.16-2.13 (m, 1H), 1.92-1.89 (m, 2H), 1.44-1.36 (m, 2H). (400MHz, MeOD) 244 3-[5-[4-[[1-[4-[6- δ 8.29(s, 2H), 7.66 (d, J = 8.4 Hz,1H), 7.53 (d, B B hydroxy-2-(4- J = 8.4 Hz, 2H), 7.16-7.10 (m, 4H), 6.95(d, J = 9.2 hydroxyphenyl)benzothio- Hz, 2H), 6.84 (d, J = 9.2 Hz, 2H),6.74 (d, J = 8.8 phen-3-yl]oxyphenyl]-4- Hz, 3H), 5.01 (dd, J = 4.2,13.8 Hz, 1H), 4.45-4.35 piperidyl]methyl]piperazin- (m, 2H), 3.54-3.48(m, 6H), 3.33-2.97 (m, 4H), 1-yl]-1-oxo-isoindolin- 2.96-2.86 (m, 1H),2.79-2.75 (m, 1H), 2.70-2.67 2-yl]piperidine-2,6-dione (m, 4H),2.51-2.40 (m, 1H), 2.16-2.12 (m, 1H), 1.94-1.84 (m, 3H), 1.46-1.41 (m,2H). (400 MHz, MeOD) 245 2-(2,6-dioxo-3- δ 8.31 (s, 1H), 7.69 (d, J =8.8 Hz, 1H), 7.53 (d, C B piperidyl)-5-[4-[[1-[4-[6- J = 8.8 Hz, 2H),7.37 (d, J = 2.4 Hz, 1H), 7.24 (dd, hydroxy-2-(4- J = 1.2, 8.4 Hz, 1H),7.16-7.13 (m, 2H), 8.95 (d, hydroxyphenyl)benzothio- J = 9.2 Hz, 2H),6.83 (d, J = 9.2 Hz, 2H), 6.77-6.73 phen-3-yl]oxyphenyl]-4- (m, 3H),6.83 (d, J = 9.2 Hz, 2H), 5.07 (d, J = 5.2, piperidyl]methyl]piperazin-12.8 Hz, 1H), 3.53-3.51 (m, 6H), 2.81-2.77 (m, 1-yl]isoindoline-1,3-1H), 2.76-2.72 (m, 5H), 2.68-2.65 (m, 3H), dione 2.49-2.47 (m, 2H),2.13-2.09 (m, 1H), 1.94-1.88 (m, 2H), 1.78 (s, 1H), 1.44-1.35 (m, 2H).(400 MHz, MeOD) *and **ER-alpha degradation measured in MCF7 cells by incell western assay method following 5 days of incubation *DC50: A < 1nM; B 1 to 10 nM; C 10-100 nM **Dmax: A > 75%; B 50% to 75%; C < 50%

SPECIFIC EMBODIMENTS OF THE PRESENT DISCLOSURE

As described above, in any aspect or embodiment described herein, thepresent disclosure provides bifunctional PROTAC compounds comprising: atleast one of benzothiophene derivative, a ER binding moiety, or acombination thereof; a linker; and at least one of a cereblon bindingligand, VHL binding ligand, IAP binding moiety, MDM2 binding moiety, ora combination thereof. The present disclosure encompasses the followingspecific embodiments. These following embodiments may include all of thefeatures recited in a proceeding embodiment, as specified. Whereapplicable, the following embodiments may also include the featuresrecited in any proceeding embodiment inclusively or in the alternative(e.g., an eighth embodiment may include the features recited in a firstembodiment, as recited, and/or the features of any of the second throughseventh embodiments).

In any aspect or embodiment described herein, wherein the compound isselected from the compounds of Table 1, 2, 3, 4, or 5 (e.g., selectedfrom Compounds 1-245).

A further aspect of the present disclosure provides a compositioncomprising an effective amount of the bifunctional compound of thepresent disclosure, and a pharmaceutically acceptable carrier.

In any aspect or embodiment described herein, the composition furthercomprises at least one of additional bioactive agent or anotherbifunctional compound of the present disclosure.

In any aspect or embodiment described herein, the additional bioactiveagent is an anti-cancer agent.

Another aspect of the present disclosure provides a compositioncomprising a pharmaceutically acceptable carrier and an effective amountof at least one compound of the present disclosure for treating adisease or disorder in a subject, the method comprising administeringthe composition to a subject in need thereof, wherein the compound iseffective in treating or ameliorating at least one symptom of thedisease or disorder.

In any aspect or embodiment described herein, the disease or disorder isassociated with estrogen receptor accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder isa cancer associated with estrogen receptor accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder isat least one of breast cancer, uterine cancer, ovarian cancer, prostatecancer, endometrial cancer, endometriosis, or a combination thereof.

In any aspect or embodiment described herein, the disease or disorder isbreast cancer.

In certain embodiments, the description provides the following exemplaryER PROTAC molecules (compounds 1-245 of Table 1, Table 2, Table 3, Table4, and Table 5), including salts, prodrugs, polymorphs, analogs,derivatives, and deuterated forms thereof. In any aspect or embodimentdescribed herein the compound of the present disclosure is selected fromTables 1, 2, 3, 4, and 5. For example, the compound may be selected fromcompounds 1-245 in any aspect or embodiment described herein.

A novel bifunctional molecule, which contains a ER recruiting moiety andan E3 Ligase Cereblon recruiting moiety, through PROTAC technology isdescribed. The bifunctional molecules of the present disclosure activelydegrades ER. PROTAC mediated protein degradation provides a promisingstrategy in targeting the “undruggable” pathological proteins bytraditional approaches.

The contents of all references, patents, pending patent applications andpublished patents, cited throughout this application are herebyexpressly incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the disclosure described herein. Such equivalents areintended to be encompassed by the following claims. It is understoodthat the detailed examples and embodiments described herein are given byway of example for illustrative purposes only, and are in no wayconsidered to be limiting to the disclosure. Various modifications orchanges in light thereof will be suggested to persons skilled in the artand are included within the spirit and purview of this application andare considered within the scope of the appended claims. For example, therelative quantities of the ingredients may be varied to optimize thedesired effects, additional ingredients may be added, and/or similaringredients may be substituted for one or more of the ingredientsdescribed. Additional advantageous features and functionalitiesassociated with the systems, methods, and processes of the presentdisclosure will be apparent from the appended claims. Moreover, thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, many equivalents to the specificembodiments of the disclosure described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A bifunctional compound having the chemicalstructure:ULM-L-PTM, or a pharmaceutically acceptable salt, enantiomer,stereoisomer, solvate, polymorph or prodrug thereof, wherein: (a) thePTM has a structure selected from the group PTM-I and PTM-II:

 wherein: X_(PTM) is O or C═O; X_(PTM1) and X_(PTM2) are eachindependently selected from N and CH; R_(PTM1) is OH, O(CO)R_(PTM), orO—C₁₋₃ alkyl, wherein R_(PTM) is an alkyl or aryl; each R_(PTM2) andR_(PTM4) is independently selected from H, OH, halogen, CN, CF₃,SO₂-alkyl, and O—C₁₋₃ alkyl; each R_(PTM3) and R_(PTM5) is independentlyselected from H and halogen; and PTM-I has at least one R_(PTM2) and atleast one R_(PTM3) on each respective rings; (b) the ULM is an E3ubiquitin ligase binding moiety, wherein: (i) the ULM is represented bythe chemical structure:

wherein: W is CH₂, CHR, C═O, SO₂, NH, or N-alkyl; each X isindependently selected from O, S, and H₂; Y is CH₂, —C═CR′, NH, N-alkyl,N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, or S; Z is O, S, orH₂; G and G′ are independently selected from H, linear or branchedalkyl, OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally substitutedwith R′, and benzyl optionally substituted with R′; each of Q₁, Q₂, Q₃,and Q₄ independently represent a N or a C substituted with a groupindependently selected from H and R; A is H, optionally substitutedlinear or branched alkyl, cycloalkyl, Cl, or F; n is an integer from 1to 4; R is —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,—CR′NR′R″—, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl,—P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I,—CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″,—C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂,—CO₂R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅, or—OCF₃, wherein on R is covalently linked to L; R′ and R″ areindependently selected from the group consisting of a bond, H,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl; and

represents a bond that may be stereospecific ((R) or (S)) ornon-stereospecific; or (ii) the ULM has the chemical structure:

wherein: X¹ and X² are each independently selected from a bond, O,NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂; R^(Y3) and R^(Y4) areeach independently selected from H, optionally substituted C₁₋₆ alkoxyland linear or branched C₁₋₆ alkyl, optionally substituted by 1 or morehalogen; R^(P) is 1, 2, or 3 groups independently selected from H,halogen, —OH, C₁₋₃ alkyl, and C═O; W³ is optionally substituted-T-N(R^(1a)R^(1b))X³, an optionally substituted -T-N(R^(1a)R^(1b)) anoptionally substituted -T-aryl, an optionally substituted -T-heteroaryl,an optionally substituted T-biheteroaryl, an optionally substituted-T-heterocycle, an optionally substituted -T-biheterocycle, anoptionally substituted —NR¹-T-aryl, an optionally substituted—NR¹-T-Heteroaryl, or an optionally substituted —NR¹-T-heterocycle; X³is C═O, R¹, R^(1a), or R^(1b); each R¹, R^(1a), and R^(1b) isindependently selected from H, R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO,R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O, N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO,N(R^(Y3)R^(Y4))SO₂, and linear or branched C₁-C₆ alkyl group optionallysubstituted by 1 or more halogen or —OH groups; T is —(CH₂)_(n)— group,wherein each one of the methylene groups is optionally substituted withone or two substituents selected from halogen, methyl, an optionallysubstituted amino acid side chain, and a linear or branched C₁₋₆ alkylgroup optionally substituted by 1 or more halogen or —OH groups; and nis an integer from 0 to 6; W⁴ is

R_(14a) and R_(14b) are each independently selected from H, haloalkyl,and optionally substituted alkyl; W⁵ is a phenyl or a 5-10 memberedheteroaryl; R₁₅ is H, halogen, CN, OH, NO₂, NR_(14a)R_(14b), OR_(14a),CONR_(14a)R_(14b), NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a)SO₂R_(14b), optionally substituted alkyl, optionally substitutedhaloalkyl, optionally substituted haloalkoxy, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl; and

indicates the site of attachment of L; and (c) the L is a bond or achemical linking group represented by -(A^(L))_(q)- that is covalentlybound to the ULM and the PTM, wherein A^(L) is a chemical linker moietyand q is an integer from 1 to
 100. 2. The bifunctional compound of claim1, wherein the ULM has the chemical structure:


3. The bifunctional compound of claim 1, wherein ULM has a chemicalstructure represented by:

wherein: W³ is an optionally substituted aryl, optionally substitutedheteroaryl, or

R₉ and R₁₀ are independently hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted hydroxyalkyl,optionally substituted heteroaryl, or haloalkyl, or R₉, R₁₀, and thecarbon atom to which they are attached form an optionally substitutedcycloalkyl; R₁₁ is optionally substituted heterocyclic, optionallysubstituted alkoxy, optionally substituted heteroaryl, optionallysubstituted aryl,

R₁₂ is H or optionally substituted alkyl; R₁₃ is H, optionallysubstituted alkyl, optionally substituted alkylcarbonyl, optionallysubstituted (cycloalkyl)alkylcarbonyl, optionally substitutedaralkylcarbonyl, optionally substituted arylcarbonyl, optionallysubstituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;R_(14a) and R_(14b) are each independently selected from H, haloalkyl,and optionally substituted alkyl; W⁵ is a phenyl or a 5-10 memberedheteroaryl; and R₁₅ is H, halogen, CN, OH, NO₂, NR_(14a)R_(14b),OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b),NR_(14a) SO₂R_(14b), optionally substituted alkyl, optionallysubstituted haloalkyl, optionally substituted haloalkoxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkyl; eachR₁₆ is independently selected from H, halogen, optionally substitutedalkyl, optionally substituted haloalkyl, hydroxy, and optionallysubstituted haloalkoxy; is 0, 1, 2, 3, or 4; each R₁₈ is independentlyselected from H, halogen, optionally substituted alkoxy, cyano,optionally substituted alkyl, haloalkyl, and haloalkoxy; and p is 0, 1,2, 3, or 4, and

indicates the site of attachment of L.
 4. The bifunctional compound ofclaim 1, wherein the ULM has a chemical structure selected from thegroup of:

wherein: R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted alkyl,optionally substituted hydroxyalkyl, optionally substituted heteroaryl,or haloalkyl; R_(14a) is H, haloalkyl, optionally substituted alkyl,methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;R₁₅ is H, halogen, CN, OH, N₀₂, optionally substituted heteroaryl,optionally substituted aryl, optionally substituted alkyl, optionallysubstituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, orcycloheteroalkyl; X is C, CH₂, or C═O; R₃ is absent or an optionallysubstituted 5 or 6 membered heteroaryl; and

indicates the site of attachment of L.
 5. The bifunctional compound ofclaim 1, wherein the CLM has a chemical structure represented by:


6. The bifunctional compound of claim 1, wherein: each A^(L) isindependently selected from a bond, CR^(L1)R^(L2), O, S, SO, SO₂,NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4),NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1),P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN),NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁cycloalkyl optionally substituted with 1-6R^(L1) and/or R^(L2) groups, C₃₋₁₁heterocyclyl optionally substitutedwith 1-6 R^(L1) and/or R^(L2) groups, aryl optionally substituted with0-6 R^(L1) and/or R^(L2) groups, heteroaryl optionally substituted with1-6 R^(L1) and/or R^(L2) groups, where R^(L1) or R^(L2), eachindependently are optionally linked to other groups to form a cycloalkylor heterocyclyl moiety, optionally substituted with 1-4 R^(L5) groups;and each R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) is independentlyselected from H, halogen, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,C₃₋₁₁heterocyclyl, OC₃₋₈cycloalkyl, SC₃₋₈cycloalkyl, NHC₃₋₈cycloalkyl,N(C₃₋₈cycloalkyl)₂, N(C₃₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH,SO₂C₁₋₈alkyl, P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂,CC—C₁₋₈alkyl, CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃, Si(OH)(C₁₋₈alkyl)₂,COC₁₋₈alkyl, CO₂H, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl,SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl, SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl,CON(C₁₋₈alkyl)₂, N(C₁₋₈alkyl)CONH(C₁₋₈alkyl),N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂, NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂,NHCONH₂, N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NHSO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, and NH SO₂NH₂.
 7. Thebifunctional compound of claim 1, wherein the L has a structure selectedfrom:—N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH₂—,—O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,—O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;—N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-;

wherein: R is H, methyl, or ethyl; X is H or F; and each m, n, o, p, q,and r of L is independently 0, 1, 2, 3, 4, 5, or 6, with the provisothat when the number is zero, there is no N—O or O—O bond.
 8. Thebifunctional compound of claim 1, wherein the L is selected from:

wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and
 20. 9. Thebifunctional compound of claim 1, wherein the L is selected from:

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and
 20. 10. Thebifunctional compound of claim 1, wherein L is selected from:


11. The bifunctional compound of claim 1, wherein the L is apolyethylenoxy group comprising from 1 to 10 ethylene glycol units,optionally substituted with aryl or phenyl.
 12. The bifunctionalcompound of claim 1, wherein the L has the chemical structure:

wherein: W^(L1) and W^(L2) are each independently a 4-8 membered ringwith 0-4 heteroatoms, optionally substituted with RQ, each RQ isindependently a H, halogen, OH, CN, CF₃, optionally substituted linearor branched C₁₋₆ alkyl, optionally substituted linear or branched C₁₋₆alkoxy, or 2 RQ groups taken together with the atom to which they areattached form a 4-8 membered ring system containing 0-4 heteroatoms;each Y^(L1) is independently a bond, optionally substituted linear orbranched C₁₋₆ alkoxy, or optionally substituted linear or branched C₁₋₆alkyl, and optionally one or more C atoms are replaced with O; n is aninteger from 0 to 10; and

indicates the attachment point to the PTM or ULM.
 13. The bifunctionalcompound of claim 1, wherein the L has the chemical structure:

wherein: W^(L1) and W^(L2) are each independently aryl, heteroaryl,cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl, biheteroaryl, orbiheterocyclic, each optionally substituted with RQ, each RQ isindependently a H, halo, OH, NH₂, NR^(Y1)R^(Y2), CN, CF₃, hydroxyl,nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, optionally substituted linearor branched C₁-C₆ alkyl, optionally substituted linear or branched C₁₋₆alkoxy, OC₁₋₃alkyl optionally substituted by 1 or more —F, or 2 RQgroups taken together with the atom they are attached to, form a 4-8membered ring system containing 0-4 heteroatoms; each Y^(L1) isindependently a bond, NR^(YL1), O, S, NR^(YL2), CR^(YL1)R^(YL2), C═O,C═S, SO, SO₂, optionally substituted linear or branched C₁-C₆ alkoxy, oroptionally substituted linear or branched C₁₋₆ alkyl, optionally one ormore C atoms are replaced with O; Q^(L) is a 3-6 membered alicyclic oraromatic ring with 0-4 heteroatoms, optionally bridged, optionallysubstituted with 0-6 R^(Q), each R^(Q) is independently H, linear orbranched C₁₋₆ alkyl optionally substituted by 1 or more halogen or aC₁₋₆ alkoxyl, or 2 R^(Q) groups taken together with the atom they areattached to, form a 3-8 membered ring system containing 0-2 heteroatoms;R^(YL1) and R^(YL2) are each independently H, OH, linear or branchedC₁₋₆ alkyl optionally substituted by 1 or more halogen or a C₁₋₆alkoxyl, or R^(YL1), R^(YL2), together with the atom to which they areattached form a 3-8 membered ring system containing 0-2 heteroatoms; nis an integer from 0 to 10; and

indicates the attachment point to the PTM or ULM.
 14. The bifunctionalcompound of claim 1, wherein the L is selected from:


15. The bifunctional compound of claim 1, wherein the compound isselected from the compounds of Table 1, 2, 3, 4, and
 5. 16. Acomposition comprising an effective amount of a bifunctional compound ofclaim 1 and a pharmaceutically acceptable carrier.
 17. The compositionof claim 16, wherein the composition further comprises at least one ofadditional bioactive agent or another bifunctional compound of claim 1.18. The composition of claim 17, wherein the additional bioactive agentis an anti-cancer agent.
 19. A method of treating a disease or disorderin a subject, the method comprising administering a compositioncomprising a pharmaceutically acceptable carrier and an effective amountof at least one bifunctional compound of claim 1 to a subject in needthereof, wherein the composition is effective in treating orameliorating at least one symptom of the disease or disorder.
 20. Themethod of claim 19, wherein the disease or disorder is associated withestrogen receptor accumulation and aggregation.
 21. The method of claim19, wherein the disease or disorder is a cancer associated with estrogenreceptor accumulation and aggregation.
 22. The method of claim 19,wherein the disease or disorder is at least one of breast cancer,uterine cancer, ovarian cancer, prostate cancer, endometrial cancer,endometriosis, or a combination thereof.
 23. The method of claim 19,wherein the disease or disorder is breast cancer.